Methods and systems for recommending an appropriate pharmacological treatment to a patient for managing epilepsy and other neurological disorders

ABSTRACT

The present invention provides systems and methods for managing epilepsy. In one embodiment, a method of the present invention characterize a patient&#39;s propensity for a future epileptic seizure and communicates to the patient and/or a health care provider a therapy recommendation. The therapy recommendation is typically a function of the patient&#39;s propensity for the future epileptic seizure.

RELATED APPLICATIONS

The present invention is related to U.S. patent application Ser. No.11/321,897, entitled “Methods and Systems for Recommending anAppropriate Action to a Patient for Managing Epilepsy and OtherNeurological Disorders”, filed Dec. 28, 2005, to Leyde et al., and U.S.patent application Ser. No. 11/322,150, entitled “Systems and Methodsfor Characterizing a Patient's Propensity for a Neurological Event andfor Communicating with a Pharmacological Agent Dispenser,” filed Dec.28, 2005, to Bland et al., the complete disclosures of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates generally to characterizing a patient'spropensity for a future neurological even and communicating with thepatient. More specifically, the present invention relates tocharacterizing a propensity for a future seizure and when it isdetermined that the patient has a high or elevated propensity for aseizure, providing a communication to the patient that is indicative ofan appropriate action for responding to the patient's elevatedpropensity for the seizure. Optionally, such information may beincorporated into an interactive communication protocol in order toconvey appropriate communications, such as instructions orrecommendations to the patient and receive historical and real-timepatient status information and acknowledgements associated with themanagement of the patient's care.

Epilepsy is a disorder of the brain characterized by chronic, recurringseizures. Seizures are a result of uncontrolled discharges of electricalactivity in the brain. A seizure typically manifests as sudden,involuntary, disruptive, and often destructive sensory, motor, andcognitive phenomena. Seizures are frequently associated with physicalharm to the body (e.g., tongue biting, limb breakage, and burns), acomplete loss of consciousness, and incontinence. A typical seizure, forexample, might begin as spontaneous shaking of an arm or leg andprogress over seconds or minutes to rhythmic movement of the entirebody, loss of consciousness, and voiding of urine or stool.

A single seizure most often does not cause significant morbidity ormortality, but severe or recurring seizures (epilepsy) results in majormedical, social, and economic consequences. Epilepsy is most oftendiagnosed in children and young adults, making the long-term medical andsocietal burden severe for this population of patients. People withuncontrolled epilepsy are often significantly limited in their abilityto work in many industries and cannot legally drive an automobile. Anuncommon, but potentially lethal form of seizure is called statusepilepticus, in which a seizure continues for more than 30 minutes. Thiscontinuous seizure activity may lead to permanent brain damage, and canbe lethal if untreated.

While the exact cause of epilepsy is uncertain, epilepsy can result fromhead trauma (such as from a car accident or a fall), infection (such asmeningitis), or from neoplastic, vascular or developmental abnormalitiesof the brain. Most epilepsy, especially most forms that are resistant totreatment (i.e., refractory), are idiopathic or of unknown causes, andis generally presumed to be an inherited genetic disorder. Demographicstudies have estimated the prevalence of epilepsy at approximately 1% ofthe population, or roughly 2.5 million individuals in the United Statesalone. Approximately 60% of these patients have epilepsy where specificfocus can be identified in the brain and are therefore candidates forsome form of a focal treatment approach.

In order to assess possible causes and to guide treatment,epileptologists (both neurologists and neurosurgeons) typically evaluatepeople with seizures with brain wave electrical analysis (e.g.,electroencephalography or “EEG” and electrocorticogram “ECoG”, which arehereinafter referred to collectively as “EEG”) and imaging studies, suchas magnetic resonance imaging (MRI). While there is no known cure forepilepsy, chronic usage of anticonvulsant and antiepileptic medicationscan control seizures in most people. The anticonvulsant andantiepileptic medications do not actually correct the underlyingconditions that cause seizures. Instead, the anticonvulsant andantiepileptic medications manage the patient's epilepsy by reducing thefrequency of seizures. There are a variety of classes of antiepilepticdrugs (AEDs), each acting by a distinct mechanism or set of mechanisms.

For most cases of epilepsy, the disease is chronic and requires chronicmedications for treatment. AEDs generally suppress neural activity by avariety of mechanisms, including altering the activity of cell membraneion channels and the propensity of action potentials or bursts of actionpotentials to be generated. These desired therapeutic effects are oftenaccompanied by the undesired side effect of sedation. Some of the fastacting AEDs, such as benzodiazepine, are also primarily used assedatives. Other medications have significant non-neurological sideeffects, such as gingival hyperplasia, a cosmetically undesirableovergrowth of the gums, and/or a thickening of the skull, as occurs withphenytoin. While chronic usage of AEDs has proven to be effective for amajority of patients suffering from epilepsy, the persistent sideeffects can cause a significant impairment to a patient's quality oflife. Furthermore, about 30% of epileptic patients are refractory (e.g.,non-responsive) to the conventional chronic AED regimens. This creates ascenario in which over 500,000 patients in the United States alone haveuncontrolled epilepsy.

If a patient is refractory to treatment with chronic usage ofmedications, surgical treatment options may be considered. If anidentifiable seizure focus is found in an accessible region of thebrain, which does not involve “eloquent cortex” or other criticalregions of the brain, then resection is considered. If no focus isidentifiable, or there are multiple foci, or the foci are in surgicallyinaccessible regions or involve eloquent cortex, then surgery is lesslikely to be successful or may not be indicated. Surgery is effective inmore than half of the cases in which it is indicated, but it is notwithout risk, and it is irreversible. Because of the inherent surgicalrisks and the potentially significant neurological sequelae fromrespective procedures, many patients or their parents decline thistherapeutic modality.

Some non-respective functional procedures, such as corpus callosotomyand subpial transection, sever white matter pathways without removingtissue. The objective of these surgical procedures is to interruptpathways that mediate spread of seizure activity. These functionaldisconnection procedures can also be quite invasive and may be lesseffective than resection.

An alternative treatment for epilepsy that has demonstrated some utilityis Vagus Nerve Stimulation (VNS). This is a reversible procedure whichintroduces an electronic device which employs a pulse generator and anelectrode to alter neural activity. The vagus nerve is a major nervepathway that emanates from the brainstem and passes through the neck tocontrol visceral function in the thorax and abdomen. VNS usesintermittent stimulation of the vagus nerve in the neck in an attempt toreduce the frequency and intensity of seizures. See Fisher et al.,“Reassessment: Vagus nerve stimulation for epilepsy, A report of theTherapeutics and Technology Assessment Subcommittee of the AmericanAcademy of Neurology,” Neurology 1999; 53:666-669. While not highlyeffective, it has been estimated that VNS reduces seizures by an averageof approximately 50% in about 50% of patients who are implanted with thedevice.

Another recent alternative electrical stimulation therapy for thetreatment of epilepsy is deep brain stimulation (DBS). Open-loop deepbrain stimulation has been attempted at several anatomical target sites,including the anterior nucleus of the thalamus, the centromedian nucleusof the thalamus, and the hippocampus. The results have shown somepotential to reduce seizure frequency, but the efficacy leaves much roomfor improvement.

There have also been a number of attempts described in the patentliterature regarding the use of predictive algorithms that purportedlycan predict the onset of a seizure. When the predictive algorithmpredicts the onset of a seizure, some type of warning is provided to thepatient regarding the oncoming seizure. For example, see U.S. Pat. No.3,863,625 to Viglione and U.S. Pat. No. 6,658,287 to Litt et al.

While conventional treatments for epilepsy have had some success,improvements are still needed.

SUMMARY OF THE INVENTION

The present invention provides improved systems and methods formonitoring, managing, and treating neurological disorders andcommunicating with a patient regarding an appropriate action. Thesystems and methods of the present invention are configured tocharacterize a patient's propensity for a future neurological event,such as an epileptic seizure.

In preferred embodiments, the present invention is for managingepilepsy—including the prevention or reduction of the occurrence ofepileptic seizures and/or mitigating their effects. The method ofpreventing an epileptic seizure comprises characterizing a patient'spropensity for a future seizure, and upon the determination that thepatient has an elevated propensity for the seizure, communicating to thepatient and/or a health care provider a therapy recommendation.

In one embodiment, a patient's propensity for a seizure can be estimatedor derived from a neural state which can be characterized as a pointalong a single or multi-variable state space continuum. The term “neuralstate” is used herein to generally refer to calculation results orindices that are reflective of the state of the patient's neural system,but does not necessarily constitute a complete or comprehensiveaccounting of the patient's total neurological condition. The estimationand characterization of “neural state” may be based on one or morepatient dependent parameters from the brain, such as electrical signalsfrom the brain, including but not limited to electroencephalogramsignals “EEG” and electrocorticogram signals “ECoG” (referred to hereincollectively as “EEG”), brain temperature, blood flow in the brain,concentration of AEDs in the brain, etc.).

In addition to using the neural state, other patient dependentparameters, such as patient history, and/or other physiological signalsfrom the patient may be used to characterize the propensity for seizure.Some of the physiological signals that may be monitored include,temperature signals from other portions of the body, blood flowmeasurements in other parts of the body, heart rate signals and/orchange in heart rate signals, respiratory rate signals and/or change inrespiratory rate signals, chemical concentrations of other medications,pH in the blood or other portions of the body, blood pressure, othervital signs, other physiological or biochemical parameters of thepatient's body, or the like).

The methods and systems of the present invention may also have thecapability to use feedback from the patient as an additional metric forcharacterizing the patient's propensity for a seizure. For example, insome embodiments, the system may allow the patient to affirm that theAED was taken, indicate that they didn't take the AED, indicate thatthey are feeling an aura or are experiencing a prodrome or othersymptoms that precede a seizure, indicate that they had a seizure,indicate that they are going to sleep or waking up, engaging in anactivity that is known to the patient to interfere with their state, orthe like.

The present invention has broad therapeutic and diagnostic applications,including the control of neural state to reduce the patient's propensityfor future neurological symptoms, as well as to the prediction of futureneurological symptoms. The present invention may use the propensity forseizure characterization to determine if an action is needed, and if anaction is needed, determine the appropriate action, and communicate theappropriate action to the patient and/or caregiver in an interactivemanner so that the management of the patient's care may be improved.

In one embodiment, the patient's characterized neural state and othercharacterized patient parameters are compared to baseline values, andthe comparison is used to determine that patient's propensity for afuture seizure. The results of the calculations and comparisons may thenbe input into a treatment algorithm, such as a fixed or configurablestate machine that implements an interactive communication protocol todetermine and convey appropriate communications (e.g., recommendationsor instructions) to the patient and/or a caregiver. However, inalternative embodiments, the systems and methods of the presentinvention may use the characterized neural state in one or more controllaws to control the neural state and/or recommend a treatment to thepatient.

Depending on the level of the patient's propensity for a seizure, thecommunication provided to the patient may take a variety of differentforms. Some embodiments will provide a recommendation or instruction totake an acute dosage of a specified pharmacological agent (e.g.,neuro-suppressant, sedative, AED or anticonvulsant, or other medicationwhich exhibits seizure prevention effects). However, the instructions orrecommendations may suggest adjusting the timing or dosage of achronically prescribed pharmacological agent, performing a specificaction such as assuming a safe posture or position, activating animplanted drug dispenser, manually activating a neuromodulationtreatment such as vagus nerve stimulation (VNS), deep brain stimulation(DBS), cortical stimulation, or the like.

In preferred embodiments, the instructions or recommendations providedby the systems and methods of the present invention will be reflectiveof, or a function of, the patient's propensity for the seizure. In someembodiments, the characterized propensity for the seizure may beindicative of an estimated time horizon until the occurrence of theseizure, a likelihood, and/or probability of the onset of the predictedepileptic seizure. The selection of the therapy and/or parameters of thetherapy will be adapted to reflect the patient's propensity for seizure.For example, if the propensity for a seizure indicates a time horizon,parameters of the therapy recommendation (such as dosage) will typicallybe inversely related to the time horizon. Thus, a higher dosage ofmedication will likely be recommended for a short time horizon than fora long time horizon. If the propensity for a seizure is indicative of alikelihood or probability for the seizure, the parameters of the therapyrecommendation will likely be directly related to the likelihood orprobability. Thus, for a high likelihood or high probability of aseizure, a higher dosage of a medication will be recommended than for alow likelihood or low probability of the seizure.

In one specific embodiment, the present invention provides a system thatcomprises a predictive algorithm that is configured to be used inconjunction with acute dosages of a pharmacological agent, including anAED, such as the rapid onset benzodiazepines. Other antiepileptic drugsor sedatives may be used as well. The predictive algorithm may be usedto characterize the patient's propensity for a future seizure. If thepredictive algorithm determines that the patient is at an increased orelevated propensity for a future seizure or otherwise predicts the onsetof the future seizure, the system may provide an output that recommendsor instructs the patient to take an acute dosage of a pharmacologicalagent (such as an AED) to prevent the occurrence of the seizure orreduce the magnitude or duration of the seizure.

As used herein, the term “anti-epileptic drug” or “AED” generallyencompasses pharmacological agents that reduce the frequency orlikelihood of a seizure. There are many drug classes that comprise theset of antiepileptic drugs (AEDs), and many different mechanisms ofaction are represented. For example, some medications are believed toincrease the seizure threshold, thereby making the brain less likely toinitiate a seizure. Other medications retard the spread of neuralbursting activity and tend to prevent the propagation or spread ofseizure activity. Some AEDs, such as the Benzodiazepines, act via theGABA receptor and globally suppress neural activity. However, other AEDsmay act by modulating a neuronal calcium channel, a neuronal potassiumchannel, a neuronal NMDA channel, a neuronal AMPA channel, a neuronalmetabotropic type channel, a neuronal sodium channel, and/or a neuronalkainite channel.

Unlike conventional anti-epileptic drug treatments, which provide for achronic regimen of pharmacological agents, the present invention is ableto manage seizures acutely while substantially optimizing the intake ofthe pharmacological agent by instructing the patient to take apharmacological agent only when it is determined that a pharmacologicalagent is necessary. Furthermore, with this new paradigm of seizureprevention, the present invention provides a new indication forpharmacotherapy. This new indication is served by several existingmedications, including AEDs, given at doses which are sub-therapeutic totheir previously known indications, such as acute AED administration forseizure termination or status epilepticus. Since this new indication isserved by a new and much lower dosing regimen and consequently a newtherapeutic window, the present invention is able to provide acorrespondingly new and substantially reduced side effect profile. Forexample, the present invention allows the use of dosages that are lowerthan FDA-approved dosages for the various anti-epileptic agents. Thisdosing may be about 5% to about 95% lower than the FDA-recommended dosefor the drug, and preferably at or below 90% of the FDA-recommendeddose, and most preferably below about 50% of the FDA-recommended dose.But as can be appreciated, if the measured signals indicate a highpropensity for a seizure, the methods and systems of the presentinvention may recommend taking an FDA or a higher than FDA approved doseof the AED to prevent the predicted seizure. Such a paradigm hasvaluable application for patients in which side effects of AEDs areproblematic, particular sedation in general and teratogenicity inpregnant women or risk of teratogenicity in all women of child bearingage.

By analogy, acetylsalycilic acid (ASA or aspirin) has a variety ofdistinct indications which are treated by distinctly different dosingregimens of the same chemical compound. For example, when given at an 81mg dosage, the anti-platelet therapeutic effect is effective as apreventative agent against cardiovascular disease. When given at a 325mg dosage, the analgesic and antipyretic effects is efficacious in painand fever control. At higher dosages of 1 to 2 grams, theanti-inflammatory effect is efficacious against rheumatoid arthritis.This exemplifies the distinctly different mechanisms of action andindications for the same chemical compound when administered atdifferent dosages with consequent different plasma levels and differenttherapeutic windows and side effect profiles. The present invention inwhich acute pharmacotherapy is provided for seizure prevention similarlyrepresents a new indication with a new dosing regimen, a new therapeuticwindow and a new side effect profile.

In another specific embodiment, the present invention provides a systemthat comprises a predictive algorithm that may be used to modify oralter the scheduling and dosing of a chronically prescribedpharmacological agent, such as an AED, to optimize or custom tailor thedosing to a particular patient at a particular point in time. Thisallows for (1) improved efficacy for individual patients, since there isvariation of therapeutic needs among patients, and (2) improved responseto variation in therapeutic needs for a given patient with time,resulting form normal physiological variations as well as from externaland environmental influences, such as stress, sleep deprivation, thepresence of flashing lights, alcohol intake and withdrawal, menstrualcycle, and the like The predictive algorithm may be used to characterizethe patient's propensity for the future seizure, typically by monitoringthe patient's neural state. If the predictive algorithm determines thatthe patient is at an increased propensity for an epileptic seizure orotherwise predicts the onset of a seizure, the system may provide anoutput that indicates or otherwise recommends or instructs the patientto take an accelerated or increased dosage of a chronically prescribedpharmacological agent. Consequently, the present invention may be ableto provide a lower chronic plasma level of the AED and modulate theintake of the prescribed agent in order to decrease side effects andmaximize benefit of the AED.

In a further embodiment, the present invention provides a method ofpreventing a predicted epileptic seizure. The method comprisesadministering an effective amount of an anti-epileptic drug to a patientin need thereof. The administration is provided at a time prior to apredicted occurrence of a seizure and the time being at least 30 secondsprior to the predicted occurrence of the seizure (and preferably atleast about 1 minute) and the effective amount of the anti-epilepticdrug is less than about 50% of a dose of the drug that is effectiveafter a seizure has occurred and the effective amount being a functionof the time prior to possible occurrence of the seizure. Some of themore rapid onset of AEDs can terminate seizures in as short a timeperiod as 30 seconds. For example, intranasal midazolam can terminate aseizure in 30 seconds, while intramuscular and IV diazepam may terminatea seizure between about 1 minute and 2 minutes.

While the particular anti-epileptic drug that is administered to thepatient will be customized to the specific patient, some preferredanti-epileptic drugs include buccal midazolam, intranasal midazolam,intramuscular midazolam, rectal diazepam, intravenous diazepam,intravenous lorazepam, and the like.

While the following discussion focuses on characterizing the patient'spropensity for a seizure and managing and treating the epilepticseizures through providing recommendations or instructions to thepatient to take an action (e.g., take an acute dosage of a medication,improved dosing of chronic medication, or other therapies for managingthe epileptic seizures), the present invention may also be applicable tocontrolling other neurological or non-neurological disorders with apredictive algorithm and the administration of other acutepharmacological agents or other acute treatments. For example, thepresent invention may also be applicable to management of Parkinson'sdisease, essential tremor, Alzheimer's disease, migraine headaches,depression, or the like. As can be appreciated, the features extractedfrom the signals and used by the predictive algorithm will be specificto the underlying disorder that is being managed. While certain featuresmay be relevant to epilepsy, such features may or may not be relevant tothe neural state measurement for other disorders.

For a further understanding of the nature and advantages of the presentinvention, reference should be made to the following description takenin conjunction with the accompanying drawings.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 illustrates a simplified method encompassed by the presentinvention.

FIG. 2 shows a simplified system that may be used to carry out themethod illustrated in FIG. 1.

FIG. 3A illustrates an embodiment of the system in which a deviceassembly is implanted in a sub-clavian pocket in the patient's body andis in communication with an intracranial electrode array, a vagus nerveelectrode, and a handheld, external patient communication assembly.

FIG. 3B illustrates an embodiment of the system in which a deviceassembly is implanted in a sub-clavian pocket in the patient's body andis in communication with a subgaleal electrode array, a vagus nerveelectrode, and a handheld, external patient communication assembly.

FIG. 4 illustrates an embodiment in which a device assembly is coupledto a patient's calvarium in the patient's body and in communication witha subgaleal electrode array, a vagus nerve electrode, and a handheld,external patient communication assembly.

FIG. 5 illustrates a simplified device assembly that is encompassed bythe present invention.

FIG. 6 is a block diagram illustrating another method encompassed by thepresent invention.

FIG. 7 illustrates a simplified predictive algorithm that may be used bythe device assembly of FIG. 5.

FIG. 8 illustrates an embodiment of a configurable communication statemachine that may be used by the patient communication assembly of FIG.7.

FIG. 9 illustrates a block diagram of a patient communication assemblyof the present invention.

FIG. 10 illustrates an embodiment of a patient communication assemblythat may be used to provide an instruction to the patient regarding anappropriate action.

FIG. 11 illustrates an embodiment of a patient communication assemblythat displays a patient's neural state index to the patient.

FIG. 12 illustrates an embodiment of a patient communication assemblythat displays a patient's target neural state and the patient's measuredneural state.

FIG. 13 illustrates an embodiment of a patient communication assemblythat displays the difference between the patient's measured neural stateand the patient's target neural state.

FIG. 14 illustrates an embodiment of a patient communication assemblythat displays an alert level to the patient. The illustrated alert levelis “normal”.

FIG. 15 is a flowchart that illustrates selection of AEDs for use withthe systems of the present invention.

FIG. 16 is an example of how an AED may have a different perturbationeffect on the neural state above and below different threshold levels.

FIG. 17 illustrates a kit that is encompassed by the present invention.

FIG. 18 illustrates a graph of left hippocampus LH and right hippocampusRH before stimulation (left) and 30 seconds after stimulation (right) ofthe left hippocampus.

FIG. 19 shows a seizure pattern observed in a rodent with chronic limbicepilepsy undergoing continuous EEG monitoring with automated seizurewarning in place.

FIG. 20 illustrates a sample response table.

FIG. 21 is a sample nomogram that illustrates a sample drug dosingversus a prediction time horizon for buccal midazolam.

FIG. 22 is a sample nomogram that illustrates a sample drug dosingversus a prediction time horizon for benzodiazepines.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides systems and methods for characterizing apatient's propensity for a future seizure and communicating an automatedprodrome, such as a recommendation to the patient regarding anappropriate action for managing (e.g., preventing, reducing a magnitude,or reducing a duration of the seizure) the future seizure. FIG. 1illustrates a simplified method 2 encompassed by the present invention.In the illustrated embodiment, one or more patient dependent parametersare received from a patient (Step 4). The one or more parameters areprocessed and if the output is undesirable in some way or is indicativeof an increased or elevated propensity for a future seizure, anappropriate action is determined that will prevent or reduce thelikelihood, magnitude, or duration of the seizure (Steps 6 and 8). Acommunication may be generated that is indicative of the appropriateaction and the communication may be provided to the patient, health careprovider, and/or caregiver of the patient (Step 9). Typically, thecommunication will be in the form of a warning, instruction, orrecommendation.

Advantageously, the methods and system of the present invention allow aphysician to customize the information or recommendations provided tothe patient. Certain patients may benefit from certain actions, whenperformed in a timeframe preceding a seizure. For example, theappropriate action is typically in the form of electrical stimulation ormanual or automatic delivery of a pharmacological agent. In preferredembodiments, parameters of the stimulation and/or pharmacological agentintervention (and the communication to the patient) may be co-related toor a function of the prediction of the seizure and customized for thepatient. For example, if the patient's propensity for the seizure is lowand/or a long time horizon is estimated for the seizure, the dosage ofthe recommended drug could be lower or the parameters of the electricalstimulation could be reduced, or the like. On the other hand, ifpatient's propensity for the seizure is high or a short time horizon isestimated for the seizure, the dosage of the recommended drug could behigher or the parameters of the electrical stimulation could beincreased. Two sample nomogram relating the dose versus a predictionhorizon is shown in FIGS. 21 and 22.

While electrical stimulation and pharmacological treatmentrecommendations are preferred actions, the present invention furtherencompasses other recommendations, such as resting, turning off thelights, performing non-repetitive tasks (or repetitive ones to induce aseizure), facial touching or other tactile stimulation, some forms ofgastrointestinal stimulation, and others. These actions may serve toreduce the likelihood, magnitude, or duration of a seizure.

Additionally, the physician can customize preventative therapy forspecific propensity levels, time horizons, probabilities, or neuralstate measurements, including making recommendations for specific dosesof certain medications that have efficacy in the prevention of seizures.This actionable information is valuable for all patients, and more sofor cognitively impaired patients; the presentation of actionableinformation elicits improved compliance in comparison to a simpleseizure prediction or probability estimation, which is more apt toelicit anxiety which can negatively impact compliance.

FIG. 2 illustrates a simplified system for carrying out the presentinvention. System 10 comprises a device assembly 12 that is incommunication with one or more patient interface assembly(s) 14, 14′.Patient interface assembly 14 typically comprises one or more electrodearrays, such as a multi-channel intracranial EEG electrode array,temperature sensors, biochemical sensors, stimulation electrodes, and/ordrug dispensing ports. If patient interface assembly 14 is used forsensing signals from the patient, signal(s) from patient interfaceassembly 14 are transmitted over a communication link to device assembly12 where the measured signal(s) are processed in order to determine apatient's propensity for the seizure, which may indicate normal neuralactivity, abnormal neural activity that is indicative of an elevatedrisk of future seizure activity, or the like. Based at least in part onthe patient's propensity for the seizure, device assembly 12 mayoptionally generate a therapeutic output signal, and automaticallydeliver a therapeutic treatment to the patient through one or more ofthe patient interface assemblies 14. The patient interface assembly 14used to deliver the therapeutic treatment may be the same patientinterface assembly 14 used for sensing the signals from the patient, orthe patient interface assembly 14 may be a different assembly.

A patient communication assembly 18 may be in wireless or wiredcommunication with device assembly 12 so as to provide a user interfacefor one-way or two-way communication between the patient and othercomponents of system 10. Patient communication assembly 18 may be usedto deliver warnings, information, recommendations, or instructions tothe patient. Optionally, patient communication assembly 18 may alsoallow the patient to provide inputs to the system 10 so as to provide aninteractive communication protocol between system 10 and the patient.The inputs from the patient may be used to indicate that a seizure hasoccurred, that the patient is having an “aura”, or the like.Additionally, the patient may indicate states of mental or physiologicalstress, sleep deprivation, alcohol consumption or withdrawal, presenceor absence of other pharmacological agents, dosing and timing ofantiepileptic drugs or other medications, each of which may alter neuralstate, seizure thresholds, and/or propensity for seizures. The patientinputs may be stored in memory and used by system 10 or clinician fortraining of the prediction algorithm.

The patient may also use patient communication assembly 18 to queryinformation from system 10; this information includes propensity forseizure, neural state, estimations for the likelihood or probability ofa seizure, estimated time horizons, and responses to pharmacologicalagents, such as antiepileptic drugs, which the patient may be takingchronically, acutely, or as part of a trial dose.

Optionally, system 10 may include a personal computer or other externalcomputing device 26 that is configured to communicate with the patientcommunication assembly 18. Personal computer 26 may allow for downloador upload of data from patient communication assembly 18 or deviceassembly 12, programming of the patient communication assembly 18 or forprogramming of the device assembly 12, or the like.

System 10 may also optionally include a clinician communication assembly20 that is in direct or indirect communication with device assembly 12.For example, clinician communication assembly may communicate withdevice assembly 12 with a direct communication link, or may communicatewith device assembly 12 indirectly through patient communicationassembly 18 (or another communication assembly (not shown)). Cliniciancommunication assembly 20 may also be in communication with a personalcomputer 26 to allow for download or upload of information fromclinician communication assembly 20, or configuration or programming ofthe clinician communication assembly 20, patient communication assembly18, device assembly 12, or the like. Clinician communication assembly 20and personal computer 26 may allow a patient's guardian or clinician toremotely monitor the patient's neural state and/or medication intake ina real-time or non-real time basis.

System 10 may also have the capability to directly or indirectly connectto the Internet 24, or a wide area network or a local area network 22 soas to allow uploading or downloading of information from patientcommunication assembly 18 or clinician communication assembly 20 to aremote server or database, or to allow a clinician or supervisor toremotely monitor the patient's propensity for seizure on a real-time ornon-real-time basis. In the illustrated embodiment, connection to theInternet is carried out through personal computers 26, but in otherembodiments, it may be possible to directly connect to the Internet 24through a communication port on patient communication assembly 18,clinician communication assembly 20, or device assembly 12.

Patient interface assembly 14 illustrated to in FIG. 2 typicallyincludes a plurality of electrodes, thermistors, or other sensors, asknown in the art. For embodiments that include electrodes, patientinterface assembly 14 may include any number of electrodes, buttypically has between about 1 electrode and about 64 electrodes, andpreferably between about 2 electrodes and about 8 electrodes. Theelectrodes may be in communication with a nervous system component(which is used herein to refer to any component or structure that ispart of or interfaced to the nervous system), a non-nervous systemcomponent, or a combination thereof. Patient interface assembly 14typically includes an array of intracranial EEG electrodes that areeither in a subgaleal location within or below the scalp and above theskull (FIGS. 3B and 4), or beneath the skull, each of which facilitatescommunication with some portion of the patient's nervous system. Someuseful areas for placing the intracranial electrodes include, but arenot limited to, the hippocampus, amygdala, anterior nucleus of thethalamus, centromedian nucleus of the thalamus, other portion of thethalamus, subthalamic nucleus, motor cortex, premotor cortex,supplementary motor cortex, other motor cortical areas, somatosensorycortex, other sensory cortical areas, Wernicke's area, Broca's area,pallido-thalamic axons, lenticulo-thalamic fiber pathway, substantianigra pars reticulata, basal ganglia, external segment of globuspallidus, subthalalmic to pallidal fiber tracts, putamen, putamen to PGefibers, other areas of seizure focus, other cortical regions, orcombinations thereof.

In addition to being placed intracranially, the patient interfaceassembly 14 may be placed extracranially and in communication with anextracranial nervous system component, such as a peripheral nerve orcranial nerve, (e.g., the vagus nerve, olfactory nerve optic nerve,oculomotor nerve, trochlear nerve, trigeminal nerve, abducens nerve,facial nerve, vestibulocochlear nerve, glossopharyngeal nerve, accessorynerve, hypoglossal nerve) or it may be coupled to other portions of thepatient's body, such as to an external surface of the patient's cranium(e.g., above, below, or within the patient's scalp).

In addition to or as an alternative to the EEG electrode array that arein communication with a nervous system component, patient interfaceassembly 14 may comprise electrodes or other sensors that are configuredto sense signals from a non-nervous system component of the patient.Some examples of such signals include but are not limited to,electromyography (EMG) signals, electrocardiogram (ECG) signals,temperature signals from the brain or other portions of the body,oximetry, blood flow measurements in the brain and/or other parts of thebody, heart rate signals and/or change in heart rate signals,respiratory rate signals and/or change in respiratory rate signals,chemical concentrations of AED or other medications, pH in the brain,blood, or other portions of the body, blood pressure, or other vitalsigns or physiological parameters of the patient's body.

As noted above, patient interface assembly 14 may also be used todeliver an electrical, thermal, optical, or medicinal therapy to anervous system component of the patient. In such embodiments, patientinterface assembly 14 may comprise one or more stimulation electrodes, amedication dispenser, or a combination thereof. The patient interfaceassembly 14 may be implanted within the patient's body or positionedexternal to the patient's body, as is known in the art.

If the patient interface assembly 14 is in the form of a medicationdispenser, the medication dispenser will typically be implanted withinthe patient's body so as to directly infuse therapeutic dosages of oneor more pharmacological agents into the patient, and preferably directlyinto the affected portion(s) of the brain. The medications willgenerally either decrease/increase excitation or increase/decreaseinhibition. Consequently, the type of drugs infused and the patient'sdisorder will affect the area in which the medication dispenser isplaced. Implanted medication reservoirs may be used, includingintracranial, intraventricular (in the cerebral ventricle), intrathecal,intravenous, and other catheters. Such embodiments include indwellingcentral venous catheters for rapid administration as well as peripheralvenous catheters. Some additional examples of medication dispensers thatcan be used with the system of the present invention are described inU.S. Pat. Nos. 6,094,598, 5,735,814, 5,716,377, 5,711,316, and5,683,422. In some embodiments, the dosage and/or timing of themedication delivery may, be varied depending on the output of thepredictive algorithm. For example, larger dosages may be provided if thepatient's propensity for a future seizure is high and smaller dosages ofmedication may be delivered if the patient's propensity for a seizure islow.

FIGS. 3A, 3B, and 4 illustrate some specific embodiments of system 10that are encompassed by the present invention. The illustrated system 10includes an implanted device assembly 12 that is positioned within thepatient's body. Typically, device assembly 12 is placed extracraniallyin a subcutaneous pocket in the patient, such as in a sub-clavicularpocket (FIGS. 3A and 3B). Alternatively, the device assembly 12 may beimplanted intracranially, or otherwise coupled to the patient's skull,such as attached to or within an opening formed in the patient'scalvarium (FIG. 4). Device assembly 12 typically comprises abiocompatible housing 25 (e.g. titanium, stainless steel, silicone,polyurethane, epoxy, or other such biocompatible material) that protectsthe internal components of the device assembly 12. While not shown, inalternative embodiments portions of device assembly 12 may be disposedexternal to the patient's body and worn on or around the patient's bodyand coupled to the implanted components. In such embodiments, deviceassembly 12 may be integrated into the same housing as the patientcommunication assembly 18 or other handheld device, or it may be in aseparate housing from the patient communication assembly 18.

Device assembly 12 may be coupled to the patient interface assemblies14, 14′ (e.g., electrodes, thermistors, and other sensors) patientcommunication assembly 18, and a clinician communication assembly (notshown) through wireless connections, wired connections, or anycombination thereof. For example, as shown in FIG. 3A, patient interfaceassembly 14 is in the form of intracranial electrodes that are used tosense intracranial EEG signals from the patient. FIG. 3B illustrates anembodiment of a subgaleal electrode array that is used to senseintracranial EEG signals. In both embodiments, implanted device assembly12 is coupled to intracranial patient interface assembly 14 throughconductive leads 21 that are tunneled through the patient's neck from anintracranial sensor head to the device assembly 12. As shown in FIG. 4,in embodiments in which the device assembly 12 is disposed in or on thepatient's head, conductive leads 21 will have a shorter path from thesensor head to the device assembly 12. Conductive leads 23 may also betunneled through the patient's body from the device assembly 12 to theimplanted patient interface assembly 14′ that is coupled to a patient'speripheral nerve, such as the vagus nerve. If device assembly 12determines that the patient is at an elevated propensity for a seizure,extracranial patient interface assembly 14′ may be used in a closed-loopfashion to selectively deliver electrical stimulation to the patient.

Device assembly 12 may transcutaneously deliver a communication outputto an external patient communication assembly 18 or a cliniciancommunication assembly 20 with a telemetry link, radiofrequency link,optical link, magnetic link, a wired link, or other wireless links. Itmay also be possible to transmit a communication output to the externalcommunication assembly 18 or clinician communication assembly 20 with awired communication link, if desired.

The parameters of the output delivered from patient interface assembly14′, whether it is the parameters of the electrical stimulation or thedosage, form, formulation, route of administration and/or timing ofdelivery of the pharmacological agent, will typically depend on thepatient's propensity for the future seizure (e.g., which may be based atleast in part on the characterized neural state). Specifically, thetherapy regimen may be varied or otherwise adapted in a closed-loopmanner, depending on the level of the patient's characterized propensityfor a seizure. In some embodiments, device assembly 12 may automaticallyactivate patient interface assembly 14 to deliver one or more modes oftherapy to the patient and closed-loop feedback will allow deviceassembly 12 to dynamically adjust the parameters of the therapy so thatthe therapy is commensurate with or a function of the patient'scharacterized propensity for a seizure. For example, the patientdependent parameters may be processed to characterize the patient'spropensity for seizure. If the propensity for seizure is elevated and isindicative of an imminent seizure, such a characterization will likelyresult in a larger magnitude of therapy than for a propensity forseizure characterization that is indicative of a longer time horizon forthe future seizure. A more complete description of systems and methodsfor delivering electrical stimulation and for providing closed-loopcontrol of a patient's state is found in commonly owned U.S. Pat. Nos.6,366,813; 6,819,956; 7,242,984; 7,277,758; 7,324,851; 7,231,254; andU.S. patent application Ser. No. 11/159,842 (filed Jun. 22, 2005), allto DiLorenzo.

FIG. 5 illustrates one embodiment of a simplified device assembly 12that is encompassed by the present invention. Device assembly 12typically carries out the methods of the present invention throughdedicated hardware components, software components, firmware components,or a combination thereof. In the illustrated embodiment, device assembly12 comprises dedicated signal processing hardware 27, e.g., ASIC(Application Specific Integrated Circuit), FPGA (Field Programmable GateArray), DSP (Digital Signal Processor), or the like, one or moreprocessors 28, and one or more memory modules 30 that are incommunication through a system bus 32. System bus 32 may be analog,digital, or a combination thereof, and system bus 32 may be wired,wireless, or a combination thereof. For ease of reference system bus 32is illustrated as a single component, but as known to those of skill inthe art, system bus 32 will typically comprise a separate data bus andpower bus. The components of device assembly 12 are configured toprocess the data received from patient interface assembly 14,characterize the patient's propensity for a seizure, generate therapysignals for patient interface assembly 14, formulate output signals tothe patient communication assembly 18, and control and coordinate mostfunctions of device assembly 12.

Memory 30 may be used to store some or all of the constructs of thesoftware algorithms and other software modules that carry out thefunctionality of the present invention. Memory 30 may also be used tostore some or all of the raw or filtered signals used to characterizethe patient's propensity for seizure, the patient's neural state, dataregarding communications to or from the patient, data regarding thepatient's history, filter settings, control law gains and parameters,therapeutic treatments, protocols, physician recommendations, or thelike. While processor 28 and memory 30 are illustrated as a singleelement, it should be appreciated that the processor 28 and memory 30may take the form of a plurality of different memory modules, in whichvarious memory modules (RAM, ROM, EEPROM, volatile memory, non-volatilememory, or any combination thereof) are in communication with at leastone of the processors 28 to carry out the present invention.

A system monitor 33 may be coupled to system bus 32. System monitor 33is configured to monitor and automatically stop or otherwise interruptprocessor 28 and provide some sort of notification to the patient in theevent that the power source in device assembly 12 has failed or is aboutto fail, or if another error in device assembly 12 has occurred.Furthermore, system monitor 33 may be coupled to a reed switch (notshown) or other means that allow the patient to manually actuate systemmonitor 33 so as to stop or start delivery of therapy or to otherwiseactuate or stop system 10. Typically, the patient may activate the reedswitch with an external magnet or wand (not shown).

Optionally, system monitor 33 may be in communication with an outputassembly 35 via system bus 32. Output assembly 35 may comprise avibratory mechanism, an acoustic mechanism, a shock mechanism, or thelike. System monitor 33 may automatically actuate output assembly 35 todeliver a vibratory signal, audio signal, or electrical shock toindicate to the patient that there an error in device assembly 12 ormaintenance is needed to the system 10. Advantageously, the output fromoutput assembly 35 may itself be useful for preventing the neurologicalevent from occurring (e.g., reduce the patient's propensity for thefuture seizure).

Processor 28 may be coupled to a system clock 36 for timing andsynchronizing the system 10. System clock 36 or additional clocks, suchas system monitor clock 36′ may also provide timing information forsystem monitor 33, or for providing timing information related totherapy delivery, recorded neural state measurements, propensity forseizure characterizations, delivery of instructions to the patient,response by the patient, time stamping of inputs from patients, or thelike.

Device assembly 12 may comprise a rechargeable or non-rechargeable powersource 37. Some examples of a power source that may be used with thedevice assembly 12 include the batteries of the type that are used topower a heart pacemaker, heart defibrillator or neurostimulator. Powersource 37 provides power to the components of device assembly 12 throughsystem bus 32. If the power source is rechargeable, a rechargingcommunication interface, such as recharging circuitry 38 will be coupledto power source 37 to receive energy from an external rechargingassembly (not shown), such as an RF transmitter or other electromagneticfield, magnetic field, or optical transmission assembly.

In addition to the recharging communication interface 38, deviceassembly 12 will typically comprise one or more additional communicationinterfaces for communicating with other components of system 10. Forexample, device assembly 12 may comprise a signal conditioning assembly40 that acts as an interface between the patient interface assembly 14and device assembly 12. Signal conditioning assembly 40 which may becomprised of hardware, software, or both, may be configured to conditionor otherwise pre-process the raw signals (e.g., EEG data, ECG data,temperature data, blood flow data, chemical concentration data, etc.)received from patient interface assembly 14. Signal conditioningassembly 40 may comprise any number of conventional components such asan amplifier, one or more filters (e.g., low pass, high pass, band pass,notch filter, or a combination thereof), analog-to-digital converter,spike counters, zero crossing counters, impedance check circuitry, andthe like.

Device assembly 12 may further comprise a therapy assembly 42 tointerface with patient interface assembly 14′ that is used to delivertherapy to the patient. Therapy assembly 42 may be comprised ofsoftware, hardware, or both, and may receive the output from processor28 (which may be the yes/no prediction of an onset of a seizure in anear term, a characterized propensity for a future seizure, probabilityoutput of a seizure, time horizon to a predicted seizure, the patient'scharacterized neural state, a signal that is indicative of the patient'sneural state, a control signal for controlling the therapy assembly, orthe like) and use the output to generate or modify the therapy that isdelivered to the patient through the patient interface assembly 14′. Thetherapy assembly 42 may include a control circuit and associatedsoftware, an output stage circuit, and any actuators including pulsegenerators, patient interfaces, electrode interfaces, drug dispenserinterfaces, and other modules that may initiate a preventative ortherapeutic action to be taken by or on behalf of the patient.

One or more communication interfaces 44 will facilitate communicationbetween device assembly 12 and a remote clinician communication assembly20, patient communication assembly 18, personal computer 26, a network22, 24, so as to allow for communication of data, programming commands,patient instructions, or the like. Communication may be carried out viaconventional wireless protocols, such as telemetry, inductive coillinks, RF links, other electromagnetic links, magnetic links, infraredlinks, optical links, ultrasound links, or the like. Communicationinterface 44 will typically include both a receiver and a transmitter toallow for two-way communication so as to allow for providing softwareupdates to device assembly 12, transmit stored or real-time data (e.g.,neural state data, propensity for seizure characterizations, raw datafrom sensors, etc.) to the patient/clinician communication assembly,transmit inputs from the patient/clinician, or the like. However, ifonly one-way communication is desired, then communication interface 44will include only one of the receiver and transmitter. Of course, inalternative embodiments in which the device assembly 12 is not fullyimplanted within the patient's body, it may be possible to provide adirect wired communication link with patient communication assembly 18.

FIG. 6 schematically illustrates a simplified method 50 that is carriedout with a system 10 of the present invention. For ease of illustratingdata processing, FIG. 6 describes using two separate algorithms that maybe run by a processor of the present invention. However, the presentinvention also encompasses a single algorithm, a combination of hardwareand software, and hardware alone that carries out the functionality ofthe two algorithms described in relation to FIG. 6.

Referring again to FIG. 6, patient signals (neural signals and otherphysiological signals) and other patient dependent parameters (such aspatient inputs and/or patient history data) that are indicative of apatient's propensity for a seizure are monitored (Step 51). Typically,the raw or pre-processed signal(s) from the patient are monitored duringa sliding observation window or epoch. The sliding windows may bemonitored continuously, periodically during predetermined intervals, orduring an adaptively modified schedule (to customize it to the specificpatient's cycles). For example, if it is known that the patient is proneto have a seizure in the morning, the clinician may program system 10 tocontinuously monitor the patient during the morning hours, while onlyperiodically monitoring the patient during the remainder of the day.Similarly, it may be less desirable to monitor a patient and provide anoutput to a patient when the patient is asleep. In such cases, thesystem 10 may be programmed to discontinue monitoring or change themonitoring and communication protocol with the patient during apredetermined “sleep time” or whenever a patient inputs into the systemthat the patient is asleep (or when the system 10 determines that thepatient is asleep). This could include intermittent monitoring,monitoring with a varying duty cycle, decreasing of the samplingfrequency, or other power saving or data minimization strategy during atime period in which the risk for a seizure is low. Additionally, thesystem could enter into a low risk mode for a time period following eachmedication dose. One exemplary method of operating a neurostimulation ordrug delivery device during a patient's sleep cycle is described in U.S.Pat. No. 6,923,784

The measured signals are input into a predictive algorithm, where one ormore features are extracted (Step 52). The extracted features and theother patient dependent parameters are classified to characterize thepatient's propensity for seizure (Step 54). If desired, a neural stateindex, which is reflective of the patient's propensity for seizure, maybe displayed to the patient or caregiver. The neural state index may bea derivative of the patient's propensity for seizure, or a simplifiedoutput of measurements performed by the predictive algorithm, and it maybe simplified to one or more scalar numbers, one or more vectors, asymbol, a color, or any other output that is indicative of differencesin the patient's neural state.

Once the patient's propensity for seizure is characterized by thepredictive algorithm, a signal that is indicative of the propensity forthe future seizure is transmitted to a treatment algorithm, where, basedat least in part on the patient's propensity for seizure, it isdetermined if any action is needed (Step 56). If an action is needed(e.g., the patient has an elevated propensity for seizure), theappropriate action is determined by the treatment algorithm using theelevated propensity for seizure (Step 57), and a communication is outputto the patient that is indicative of the appropriate action for thepatient to take (Step 58).

In the simplest embodiment, the predictive algorithm provides an outputthat indicates that the patient has an elevated propensity for seizure.In such embodiments, the communication output to the patient may simplybe a warning or a recommendation to the patient that was programmed intothe system by the clinician. In other embodiments, the predictivealgorithm may output a graded propensity assessment, a quantitativeassessment of the patient's state, a time horizon until the predictedseizure will occur, or some combination thereof. In such embodiments,the communication output to the patient may provide a recommendation orinstruction that is a function of the risk assessment, probability, ortime horizon.

FIG. 7 illustrates one embodiment of a predictive algorithm 60 that isencompassed by the present invention. Predictive algorithms 60 areroutinely considered to be comprised of arrangements of featureextractors or measures 62, and classifiers 64. Feature extractors 62 areused to quantify or characterize certain aspects of the measured inputsignals. Classifiers 64 are then used to combine the results obtainedfrom the feature extractors into an overall answer or result. Algorithmsmay be designed to detect different types of conditions of which neuralstate may be reflective. These could include but are not limited toalgorithms designed to detect if the patient's neural state indicativeof an increased propensity for a seizure or algorithms designed todetect deviation from a normal state. As can be appreciated, for otherneurological or non-neurological disorders, the patient's neural statewill be based on algorithms, feature extractors and classifiers that aredeemed to be relevant to the particular disorder.

As shown in FIG. 7, in use, signals from patient interface assembly 14may be transmitted to predictive algorithm from the patient interfaceassembly, as described above. The signals may be first pre-processed bythe signal conditioning assembly 40 (FIG. 5), or predictive algorithm 60itself may have a pre-conditioning component (not shown). In onepreferred embodiment, the predictive algorithm 60 comprises featureextractors for brain signals (e.g., EEG signals, brain temperaturesignals, brain blood flow, etc.) that are used to characterize thepatient's neural state and feature extractors for other patientparameters (e.g., non-brain, physiological signals, patient history,patient inputs). The predictive algorithm typically uses somecombination of the brain signal and other patient parameters tocharacterize the patient's propensity for seizure, but it may bepossible that only the brain signals (e.g., neural state) or only theother patient parameters may be used to characterize the patient'spropensity for seizure.

Feature extractors 62 receive the signals and extract variousquantifiable features or parameters from the signal to generate anoutput for classifier 64. Feature extractor 62 may extract univariateand bivariate measures and may use linear or non-linear approaches.While the output from feature extractor 62 may be a scalar, the outputis typically in the form of a multivariable feature vector. As shown inFIG. 7, each of the features themselves may be combined with otherfeatures and used as inputs for a separate feature extractor. Forexample, in the illustrated example, the output from Feature Extractor#1 and the output from Feature Extractor #2 are used as inputs intoFeature Extractor #4. Any number of different feature extractors may beused to characterize the patient's propensity for a seizure. Differentcombinations of features and/or different features themselves may beused for different patients to characterize the patient's propensity forthe future seizure. Furthermore, it may be desirable to customize thepredictive algorithm to the patient so that only selected features areextracted and/or sent to the classifier.

Some examples of potentially useful features to extract from the signalsfor use in determining the patient's propensity for the seizure, includebut are not limited to, alpha band power (8-13 Hz), beta band power(13-18 Hz), delta band power (0.1-4 Hz), theta band power (4-8 Hz), lowbeta band power (12-15 Hz), mid-beta band power (15-18 Hz), high betaband power (18-30 Hz), gamma band power (30-48 Hz), second, third andfourth (and higher) statistical moments of the EEG amplitudes, spectraledge frequency, decorrelation time, Hjorth mobility (HM), Hjorthcomplexity (HC), the largest Lyapunov exponent L(max), effectivecorrelation dimension, local flow, entropy, loss of recurrence LR as ameasure of non-stationarity, mean phase coherence, conditionalprobability, brain dynamics (synchronization or desynchronization ofneural activity, STLmax, T-index, angular frequency, and entropy), linelength calculations, area under the curve, first, second and higherderivatives, integrals, or a combination thereof. Some additionalfeatures that may be useful are described in Mormann et al., “On thepredictability of epileptic seizures,” Clinical Neurophysiology 116(200) 569-587.

Once the desired features are extracted from the signal 52, the at leastsome of the extracted features (and optionally other patient dependentparameters, such as patient history, patient inputs, and/or other directphysiological signals from the patient) are input into one or moreclassifiers 64, where the feature vector (or scalar) is examined so asto classify the patient's propensity for a future seizure (e.g., neuralstate). The classifier 64 classifies the measured feature vector toprovide a logical answer or weighted answer. The classifier 64 may becustomized for the individual patient and the classifier may be adaptedto use only a subset of the features that are most useful for thespecific patients. Additionally, over time, as the system adapts to thepatient, the classifier 64 may reselect the features that are used forthe specific patient.

In order to provide the classifications for the classifier 64, aninducer 66 may use historical/training feature vector data toautomatically train the classifier 64. The inducer 66 may be used priorto implantation and/or may be used to adaptively monitor the neuralstate and dynamically adapt the classifier in vivo.

Using any of the accepted classification methods known in the art, themeasured feature vector is compared to historical or baseline featurevectors to classify the patient's propensity for a future epilepticseizure. For example, the classifier may comprise a support vectormachine classifier, a predictive neural network, artificial intelligencestructures, a k-nearest neighbor classifier, or the like.

As it relates to epilepsy, one implementation of the classification ofstates defined by the classifier may include (1) a “normal” state orinter-ictal state, and (2) an “abnormal” state or pre-seizure state(sometimes referred to herein as “pre-ictal state”), (3) a seizure stateor ictal state, and (4) a post-seizure state or post ictal state.However, since the primary purpose of the algorithm is to determine ifthe patient is in a “normal state” or “abnormal state,” it may bedesirable to have the classifier only classify the patient as being inone of the two most important states—a pre-ictal state or inter-ictalstate—which could correspond to a high propensity for a future seizureor a low propensity for a future seizure.

As noted above, instead of providing a logical answer, it may bedesirable to provide a weighted answer so as to further delineate withinthe pre-ictal state to further allow system 10 to provide a morespecific output communication for the patient. For example, instead of asimple logical answer (e.g., pre-ictal or inter-ictal) it may bedesirable to provide a weighted output in the form of a simplifiedneural state index (NSI) or other output that quantifies the patient'spropensity, probability, likelihood or risk of a future seizure usingsome predetermined scale (e.g., scale of 1-10, with a “1” meaning“normal” and a “10” meaning seizure is imminent). For example, if it isdetermined that the patient has an increased propensity for a seizure(e.g., patient has entered the pre-ictal state), but the seizure islikely to occur on a long time horizon, the output signal could beweighted to be reflective of the long time horizon, e.g., an NSI outputof “5”. However, if the NSI indicates that the patient is in a pre-ictalstate and it is predicted that the seizure is imminent within the next10 minutes, the output could be weighted to be reflective of the shortertime horizon to the seizure, e.g., an NSI output of “9.” On the otherhand, if the patient's neural state is normal, the algorithm may providean NSI output of “1”.

Another implementation involves expressing the inter-ictal and pre-ictalstates as a continuum, with a scalar or vector of parameters describingthe actual state and its variation. Such a continuous variable or set ofvariables can be communicated to the patient, enabling the patient toemploy his or her own judgment and interpretation to then guidepalliative or preventative behaviors or therapies or the continuousvariable or set of variables may be used by the system 10 of the presentinvention to determine and recommend an appropriate therapy based on thepatient's state within the continuum.

Once the classifier has classified the patient's propensity for seizure,(e.g., elevated/pre-ictal or normal/not pre-ictal) the output from theclassifier is transmitted to the treatment algorithm, such as aconfigurable communication state machine (see for example, FIG. 8),where the appropriate action is determined.

The predictive algorithms and treatment algorithms may be embodied in adevice that is implanted in the patient's body, external to thepatient's body, or a combination thereof. For example, in one embodimentthe predictive algorithm may be stored in memory 30 and processed inprocessor 28, both of which are in a device assembly 12 that isimplanted in the patient's body. The treatment algorithm, in contrast,may be processed in a processor that is embodied in an external patientcommunication assembly 18. In such embodiments, the patient's propensityfor seizure characterization (or whatever output is generated by thepredictive algorithm that is predictive of the onset of the seizure) istransmitted to the external patient communication assembly, and theexternal processor performs any remaining processing to generate anddisplay the output from the predictive algorithm and communicate this tothe patient. Such embodiments have the benefit of sharing processingpower, while reducing the battery usage of the implanted assembly 12.Furthermore, because the treatment algorithm is external to the patient,updating or reprogramming the treatment algorithm may be carried outmore easily.

In other embodiments however, both the predictive algorithm and thetreatment algorithm may be processed by processor 28 and/or hardware 27that are implanted within the patient, and an output signal istransmitted to the patient communication assembly 18, where the outputsignal may or may not undergo additional processing before beingcommunicated to the patient. Such a configuration minimizes the datatransmission route and reduces potential bandwidth issues with thetelemetry communication between the device assembly 12 and the patientcommunication assembly. Furthermore, if the appropriate action isautomatically facilitated by the device assembly 12, such treatment maybe provided even if the patient communication assembly 18 isnon-functional or lost.

Alternatively, it may be possible that most or all of the processing ofthe signals measured by patient interface 14 is done in a device that isexternal to the patient's body. In such embodiments, the implanteddevice assembly 12 would receive the signals from patient interface 14and may or may not pre-process the signals and transmit some or all ofthe measured signals transcutaneously to an external patientcommunication assembly 18, where the prediction of the seizure andtherapy determination is made. Advantageously, such embodiments reducethe amount of computational processing power that needs to be implantedin the patient, thus potentially reducing power consumption andincreasing battery life. Furthermore, by having the processing externalto the patient, the judgment or decision making components of the systemmay be easily reprogrammed or custom tailored to the patient withouthaving to reprogram the implanted device assembly 12.

In yet other embodiments of the present invention, it may be possible toperform some of the prediction in the implanted device assembly 12 andsome of the prediction and treatment determination in an externaldevice, such as the patient communication assembly 18. For example, oneor more features from the one or more signals may be extracted withfeature extractors in the implanted device assembly 12. Some or all ofthe extracted features may be transmitted to the patient communicationassembly, where the features may be classified to predict the onset of aseizure. Thereafter, an appropriate action (if needed) may be determinedby the treatment algorithm (which may be stored in the device that isimplanted in the patient's body or in a device that is external to thepatient's body). If desired, patient communication assembly 18 may becustomizable to the individual patient. Consequently, the classifier maybe adapted to allow for transmission or receipt of only the featuresfrom the implanted device assembly 12 that are predictive for thatindividual patient. Advantageously, by performing feature extraction inthe implant and classification in the external device at least twobenefits may be realized. First, the wireless data transmission ratefrom the implanted device assembly 12 to the patient communicationassembly 18 is reduced (versus transmitting pre-processed data). Second,classification, which embodies the decision or judgment component, maybe easily reprogrammed or custom tailored to the patient without havingto reprogram the implanted device assembly 12.

In yet another embodiment, it may be possible to switch the positions ofthe classifier and the feature extractors so that feature extraction maybe performed external to the body. Pre-processed signals (e.g.,filtered, amplified, conversion to a digital signal) may betranscutaneously transmitted from device assembly 12 to the patientcommunication assembly 18 where one or more features are extracted fromthe one or more signals with feature extractors. Some or all of theextracted features may be transcutaneously transmitted back into thedevice assembly 12, where a second level of processing may be performedon the features, such as classifying of the features (and other signals)to characterize the patient's propensity for the onset of a futureseizure. Thereafter, the patient's propensity for the future seizure orother answer may be transmitted to the treatment algorithm (which may bein the device assembly 12 or the patient communication assembly 18) todetermine an appropriate action (if needed). If desired, to improvebandwidth, the classifier may be adapted to allow for transmission orreceipt of only the features from the patient communication assemblythat are predictive for that individual patient. Advantageously, becausefeature extractors may be computationally expensive and power hungry, itmay be desirable to have the feature extractors external to the body,where it is easier to provide more processing and larger power sources.

FIG. 8 shows one example of a state machine that may be used with thepresent invention. As shown in FIG. 8, a configurable communicationstate machine is responsive to the Neural State Index or other output ofthe predictive algorithm, patient inputs and other variables such astime-of-day. The outputs from the configurable communication statemachine may vary depending on the machine state. Some output behaviorsmay be fixed, and some output behaviors may be configurable. Forexample, a clinician could configure a different set of prompts for apatient who is considered to be sleeping 70 than for when the samepatient is considered to be awake 72. Moreover, the clinician canprogram a different set of prompts depending on any of the patientdependent parameters. For example, if the patient indicates that theyrecently had an aura, the configurable state machine may be adapted tovary the machine state and provide different sets of prompts orthresholds.

In the illustrated example, a standard mode for the state machine inwhich the patient's propensity for seizure is monitored is an Awake IdleState 72. If and when the patient's propensity for seizure reaches oneor more thresholds that are indicative of an elevated propensity of aseizure, the state machine moves to an “Instruct Patient—Wake Mode” 73in which a fixed and/or configurable instruction is communicated to thepatient depending on the patient's characterized propensity for seizure(see FIG. 8). The instruction may take the form of an audio prompt, avisual prompt, a text prompt, a mechanical prompt, or a combinationthereof. As described herein, the instructions may recommend that thepatient take an acute dosage of an AED or other pharmacological agent,activate a vagus nerve stimulator or other stimulator, activate athermal cooling device, make themselves safe, or the like. Theinstructions will continue until the patient acknowledges theinstruction. The state machine will continue monitoring the patient'spropensity for seizure to register any change in propensity for seizure(resulting from implementation of the instructions or otherwise) and todetermine whether any further instructions are required. Optionally,once the patient acknowledges the instruction 75, the state machine mayemit an acknowledgement mode fixed and/or configurable output to thepatient. Such acknowledgement output may be an audio prompt, visualprompt, text prompt, mechanical prompt, or a combination thereof.

As shown in FIG. 8, it may be desirable to change from an Awake State toa Sleep State. For example, some patient's may have more frequentseizures during their sleep cycle, while other patients may have fewerseizures during their sleep cycle. Thus for the different patients itmay be desirable for the clinician to customize the types ofcommunication provided to the patient, the specific instructionsprovided to the patient, the frequency of monitoring the propensity forseizure during the patient's sleep cycle, or the like. Thus, in theillustrated embodiment, if the patient is going to sleep and activates asleep button or if the state machine determines that the patient issleeping, the state machine enters the Sleeping Idle State 70. When thepatient is sleeping and the patient's propensity for seizure measurementreaches one or more defined thresholds that are indicative of a higherpropensity for a future seizure (which may be the same thresholds ordifferent thresholds from the Awake Idle State 72), the state machinemay enter an “Instruct Patient—Sleep Mode” 71, in which a fixed and/orconfigurable instruction is provided to the patient. The instruction tothe patient may include an audio prompt, visual prompt, text prompt,mechanical prompt, or a combination thereof. Similar to the InstructPatient—Wake Mode 73, when the state machine is in the InstructPatient—Sleep Mode 71, the instructions will continue until the patientacknowledges the instruction. Once the patient acknowledges theinstruction 75, the state machine may return to the Awake Idle State 72.

If the patient awakes from sleep, the patient may press an awake buttonor other input device on the patient communication assembly 18 to changethe state machine from the Sleeping Idle State 70 to the Awake IdleState 72. Alternatively, the state machine may be programmed to changeto the Awake Idle State 72 when an awake interval is reached.Optionally, an alarm clock 74 may be integrated as a method for furtherascertaining whether or not the patient is asleep. Furthermore, thestate machine may itself automatically transition from a Sleeping IdleState 70 to and Awake Idle State 72 when certain conditions are present.In the Sleeping Idle State, a low-power mode may calculate anapproximation of the propensity for seizure, and if certain ranges orbehaviors of the propensity for seizure are detected, then the systemmay automatically transition from the Sleeping Idle State 70 to theAwake Idle State 72, where the “full power” mode may be used tocharacterize the patient's propensity for seizure.

While the configuration communication state machine of FIG. 8 is oneembodiment for providing an instruction or recommendation to the patientbased on the patient's propensity for seizure, in other embodiments, atreatment algorithm may be embodied in an embedded microprocessor toprocess linear or nonlinear control laws and may also use the outputfrom the predictive algorithm to provide a communication output to thepatient and/or generate or adjust a magnitude of the therapy (e.g., anelectrical stimulation signal or the type or amount of medicationdelivered). Some examples of useful means for generating the therapy oroutput to the patient may be found in commonly owned U.S. Pat. Nos.6,366,813 and 6,819,956.

It is contemplated that the predictive algorithms and treatmentrecommendations specified by the clinician are likely to be customizedfor each individual patient. As such, the number and/or type of featuresextracted, the, the classifier, the types of treatment prescribed willlikely be customized for the patient. Moreover, it may be desirable tohave the predictive algorithm adapt to the patient over time, and modifythe feature extractors to track the patient's propensity for seizurechanges over time.

While FIGS. 7-8 illustrate exemplary algorithms of the presentinvention, a variety of other predictive algorithms and treatmentalgorithms may be useful with the systems 10 of the present invention topredict the onset of an epileptic seizure. Some examples of other usefuldetection or prediction algorithms include those described in U.S. Pat.No. 3,863,625 to Viglione, U.S. Pat. No. 6,658,287 to Litt, U.S. Pat.No. 5,857,978 to Hively, and U.S. Pat. No. 6,304,775 to Iasemidis, U.S.Pat. No. 6,507,754 to Le Van Quyen et al., U.S. Pat. No. 6,594,524 toEsteller et al. Any of such detection and prediction algorithms may beused by system 10 of the present invention to produce an output that maybe used by the treatment algorithm to determine the communication (e.g.,recommendation or instruction) that is output to the patient. Forexample, one or more probability outputs or time horizons of Litt's '978algorithm may be used to determine the appropriate action output that isprovided to the patient. Thus, while the above description describesusing a neural state to characterize the patient's propensity for afuture seizure, any of the outputs provided by the prediction algorithmsdescribed in the aforementioned patents may be used to characterize thepatient's propensity for the future seizure.

FIG. 9 schematically illustrates a patient communication assembly 18 ofthe present invention that may house a portion of or all of thealgorithms of the present invention and/or provide the outputcommunication to the patient. Patient communication assembly 18 willtypically be in the form of an external, handheld device. If desired,the patient communication assembly 18 may be integrated with otherhandheld devices, such as a cellular phone, pager, personal digitalassistant (PDA), glucose monitor, MP3 or other audio or video player,wristwatch, portable gaming device, or the other handheld devices.However, as can be appreciated, the patient communication assembly 12does not have to be handheld and may be incorporated into a personalcomputer or workstation.

Patient communication assembly 18 generates the output to the patientusing software, hardware, or a combination thereof. Patientcommunication assembly 18, typically comprises one or more processors80, a processor clock 81, one or more permanent or removable memorymodules 82 (e.g., RAM, ROM, EEPROM, flash memory, or the like),dedicated signal processing hardware 84, and a power source/battery 85.A system bus 86 may provide a communication path and power path for thevarious components of patient communication assembly 18. Memory modules82 may be use to store one or more algorithms used by patientcommunication assembly 18 and/or to store data transmitted from signalprocessing device 12. In addition to memory modules, patientcommunication assembly 18 may comprise a memory card slot 89 forreceiving a removable memory card 91, such as a flash memory stick.

A patient input assembly 87 allows a patient to communicate withprocessor 80 and device assembly 12. Patient communication assembly 18may include any number of patient inputs that allows the patient toquery device assembly 12 and to provide inputs into system 10. Someuseful inputs include buttons, levers, switches, touchscreen, touchpad,joystick, wheel, dial, an alphanumeric keypad, or the like. User inputsmay be used by the patient to turn off an alarm, activate therapy (e.g.,manually activate electrical stimulation or drug delivery), indicatethat a pharmacological agent has been taken, scroll through menus,provide an indication to system 10 that a seizure is occurring or aboutto occur, or the like.

Advantageously, the present invention will allow the patient to provideinputs to provide patient feedback into system 10 that may be used bythe prediction algorithm 60 (FIG. 7) as a “feature” to improve thecharacterization of the patient's propensity for the future seizure.Additionally, the inputs provided by the patient may be stored in memory82 and used as a “diary” to allow for later analysis by the clinicianand/or device assembly. Additional information that may be input includepatient state, such as sleep deprivation, exposure to or “withdrawal”from alcohol or other medications, physiological or emotional stress,presence or absence of antiepileptic drugs (AEDs) or other medications,start of menstrual cycle, or the like. Since many patients have aurasprior to having a seizure, the input from the patient into the systemthat indicates that an aura is occurring may be used by algorithm 60 tocharacterize the patient's propensity or by the treatment algorithm todetermine the appropriate treatment.

Patient communication assembly 18 may include one or more communicationports 88 that facilitate communication with the device assembly 12. Thedata from device assembly 12 is preferably transmitted substantially inreal time from the device assembly 12 to the patient communicationassembly 18. Communication port 88 provides for one-way or two waytranscutaneous communication with the implanted device assembly 12through conventional wireless communication protocols, such as throughtelemetry, radiofrequency, ultrasonic, optical, or magneticcommunication protocols.

Communication port 88 may further facilitate wireless or wiredcommunication with other external devices or networks. For example, thecommunication port may be used to communicate with cliniciancommunication assembly 20, a LAN, a WAN, the Internet, a local or remoteserver/computer 26, or the like (FIG. 2). Communication with a networkwould allow for downloading of patient history data (e.g., neural state,medication intake, etc.) to a remote server for future or substantiallyreal-time review by a clinician or the patient's guardian. Furthermore,software updates or parameter changes for the patient communicationassembly 18 or the signal processing device 12 may be transmitted anduploaded to the system 10 via communication port 88.

Patient communication assembly 18 will comprise a patient outputassembly 90 that includes one or more output mechanisms forcommunicating with the patient. Patient output assembly 90 may includean audio mechanism, a vibratory mechanism, a visual mechanism (e.g.,LEDs, LCD, or the like), or any combination thereof. Patientcommunication assembly 18 will be programmed to deliver a plurality ofdifferent outputs to the patient, in which each of the different outputswill be reflective of either a different propensity for seizure or adifferent action that the patient should take. For example, it may bedesirable to provide different patterns or intensities of beeps,flashing lights or vibrations to be indicative of different propensityfor seizures or neural states. Some examples of different outputs thatmay be provided to the patient are described more fully below.

In some embodiments, patient communication assembly 18 may include acharging assembly (not shown) for charging the power source 85 of theimplanted device assembly 12. The charging assembly may be placed aboveor against the patient's skin where the device assembly is implanted andactivated to interact with the recharging communication interface tocharge the power source 85. Of course, in other embodiments, theexternal recharging assembly may be a separate device.

While not shown in FIG. 9, a clinician communication assembly willtypically have similar or a superset of the components in theillustrated patient communication assembly 18. A significant differencebetween the patient communication assembly 18 and the cliniciancommunication assembly is that the clinician communication assembly 20may be used as a programmer that allows a clinician or supervisor toreprogram device assembly 12. The clinician may update the software ofdevice assembly 12, update the treatment algorithm, change theparameters of the recommended therapies, change the outputs provided tothe patient, change the clinician defined recommendations/instructions,or the like. Clinician communication assembly 20 does not have to be ahandheld device, and it may be desirable to allow the clinician tomonitor a variety of different patients with a single device.Consequently, it may be desirable to have the clinician communicationassembly be in the form of a personal computer or other device that isable to communicate with patient communication assembly 18.

When communication with the implanted device assembly 12 is desired, aprogramming device, such as clinician communication assembly 20 isbrought into a communication range with the device assembly 12 or thepatient communication assembly 18. This may be achieved simply byplacing the programming device above or against the patient's skin wherethe device assembly 12 is implanted in the patient. The communicationport of the clinician communication assembly 20 transmits data to andfrom the communication port 44 of device assembly 12 via conventionalwireless protocols, such as telemetry, inductive links, magnetic links,RF links, infrared links, optical links, ultrasound links, or the like.Alternatively, it may be possible to provide for indirect communicationwith implanted device assembly 12 via the patient communication assembly18. Reprogramming of device assembly 12 may be indirectly achieved bysending programming instructions from the clinician communicationassembly 20 (or personal computer 26 (FIG. 2)) to the patientcommunication assembly 18 through a wired or wireless communicationlink. Thereafter, the programming data may be transmitted wirelesslyfrom patient communication assembly 18 to the device assembly 12 usingconventional protocols or any of the communication protocols describedabove.

In certain embodiments, it may be possible to automatically contact thepatient's clinician with the device assembly 12 and/or patientcommunication assembly 18. For example, if a specified threshold isreached, a seizure of sufficient duration has occurred, a sufficientquantity of seizures has occurred, a maximum amount of pharmacologicalagent has been taken within a predetermined time period, or anundesirable state is reached, the patient communication assembly 18 mayinitiate a communication link (e.g., a call, email, text message, etc.)to the clinician communication assembly 20 or other remote server. Ifdesired, the communication may include the patient's neural state data,propensity for seizure, instructions provided to the patient,pharmacological agent intake, or any other data generated or stored bysystem 10. Such a communication may take place in real time, or within adelayed time period that would still allow the patient and/or clinicianto take the appropriate action.

While the patient communication assembly illustrated in FIG. 9 comprisesa plurality of digital components, the present invention is not limitedto such a configuration, and the patient communication assembly may becarried out with a different combination of components, e.g., differentcomponents, additional digital components, fewer digital components, acombination of digital components and analog circuitry, solely analogcircuitry, or the like.

FIG. 10 illustrates one embodiment of a simplified handheld patientcommunication assembly 18 that is encompassed by the present invention.Patient communication assembly comprises a housing 92 that is sized andshaped to be held in a patient's hand. Housing 92 includes a patientinput assembly that comprises one or more input devices. In theillustrated embodiment, the patient communication assembly comprises aplurality of buttons 94, a touch screen 95, and a scroll wheel 96 thatallows a patient to provide inputs into system 10, query device assembly12, scroll through display menus, and the like. Communications to thepatient may be provided to the patient through patient output assembly,which includes the touch screen display 95, speaker 98, and a vibrationmechanism (not shown). Patient communication assembly 18 will typicallyhave the following communication ports—a charging port 100 coupled tothe power source, a USB port 102 or other port for providing wired orwireless communication with a host computer, and communication port 88for communicating with the implanted device assembly 12. Optionally,patient communication assembly may comprise slot 89 for receiving aremovable memory, such as a flash memory stick.

As shown in FIG. 10, patient communication assembly 18 preferablyprovides a visual communications to the patient via screen 95, but ascan be appreciated it may be desirable to provide an auditory, vibratoryor other output in addition to or as an alternative to the visualdisplay. Screen 95 may display to the patient an output 105 that isindicative of the appropriate action to take. Display 95 may also beused to display other data to the patient, such as battery power 106,time 108, error messages 110, or the like. While not shown, patientcommunication assembly 18 may comprise a menu driven interface thatallows the patient to toggle from a home screen display to other displayscreens. Such an interface would allow the patient to access other menusand sub-menus that have additional information that the patient may finddesirable. Such a menu structure would allow more advanced users toaccess more detailed information, while providing less advanced users adisplay of the most relevant information on the home screen. Forexample, the sub-menus may include historical information on thepatient's drug intake, estimations of the drug plasma levels, number ofseizures over a time period, duration of seizures, the patient'sreal-time neural state, propensity for seizure, a time history of thepatient's neural state, other information relating to neural state andresponse to therapy, and the like. If desired, the menu interface may becustomizable to suit the patient's preferences. The communicationassembly 18 may also provide information to the patient relating to theestimated effect or response to chronic or acute therapy and may makeadjustments to these recommendations including recommendations foraugmentative or supplementary therapy, with the same or additionalmedications or other modalities. Recommendations for behavioralmodification may also be provided, these including recommendations toavoid hazardous activities such as driving or operating machinery orcooking, to sit in a quiet dark room, to rest, or to avoid walkingoutside or going to work that day.

The output 105 that is indicative of the appropriate action may specifyany number of different actions, depending on the output from thepredictive algorithm and therapy regimen prescribed by the clinician. Inmost cases, the therapy regimen prescribed by the clinician will includethe use of one or more pharmacological agents, such as an anticonvulsantor anti-epileptic drug. As such, in the simplest embodiment, when system10 determines that the patient has an elevated propensity for a seizure,patient communication assembly 18 may provide a warning, and the patientwill know to take a certain dosage of a specified pharmacological agent.In preferred embodiments, however, the patient communication assembly 18outputs a communication which recommends that the patient take one ormore pharmacological agents and may specify the dosage or otherparameters of the pharmacological agent.

In embodiments where the predictive algorithm is able to provide aweighted answer and provide a greater specificity regarding thepre-ictal state (e.g., the NSI), the output to the patient may also beindicative of a graded response, such as the dosage, form, formulation,and/or route of administration for the pharmacological agents. Dependingon the output from the predictive algorithm, the patient communicationassembly may recommend that the patient take a lower than normal dosage(e.g., ½ a normal dosage), a normal dosage or a higher than normaldosage (e.g., 2× the normal dosage) of a pharmacological agent. Forexample, if the patient's propensity for a seizure (or probability for aseizure) is low and/or there is a long predicted time horizon before theseizure occurs, depending on the clinician's and patient's preference,the patient communication assembly 18 may be configured to output arecommendation that the patient to take a lower than normal dosage of apharmacological agent or a milder type of pharmacological agent that hasless severe side effects than the patient's primary pharmacologicalagent(s). However, if the lower than normal dosage of thepharmacological agent or the milder pharmacological agent, either ofwhich may be considered to be a “preventative dose”, does not reduce thepatient's propensity for the seizure and the patient continues to trendtoward a seizure, (or if the system initially determines a highpropensity or probability of a seizure or a short time horizon for theseizure) the patient communication assembly 18 may output arecommendation that the patient take a more severe action, such astaking an additional dose or a higher than normal dosage of thepharmacological agent or a more potent type of pharmacological agent.

In addition to prescribing a dosage of the pharmacological agent, theoutput to the patient may also specify a time for taking thepharmacological agent and/or a form of the pharmacological agent. Ifsystem 10 determines that there is a moderate propensity, moderateprobability of a seizure, or there is a long predicted time horizonbefore the next seizure will occur the patient may be instructed to takea slower acting pharmacological agent or a slower acting form of apharmacological agent within a specified time period (e.g., within thenext 20 minutes). On the other hand, if system 10 determines that thereis a high propensity of seizure, high probability of a seizure, or ifthe predicted time horizon is short, the patient may be instructed totake a faster acting type of pharmacological agent or a faster actingform of a pharmacological agent within a shorter specified time period(e.g., within the next 5 minutes). Such faster acting pharmacologicalagents may include sublingual medications, intranasal medications,intramuscular injections, intravenous injections, or other injections orroutes of administration.

The output to the patient is not limited to recommending or instructingthe patient to take a pharmacological agent. An instruction to performany accepted means for managing or treating epileptic seizures may beoutput to the patient. For example, if the seizure is imminent and islikely not to be averted with electrical stimulation or pharmacologicalagents, the communication device 18 may warn the patient of the imminentseizure and simply instruct the patient to “make themselves safe.” Thiswould allow the patient to stop driving, lie down, stop cooking, or thelike. Some additional instructions or outputs that may be provided tothe patient include, but are not limited to, turning off lights,interrupting work, touching the face, hyperventilating, hypoventilating,holding breath, performing the valsalva maneuver, applying an externalstimulator (e.g., lights, electrical stimulation, etc.), applyingtranscutaneous electrical neurostimulation, applying tactilestimulation, activating an implanted deep brain neurostimulator,activating an implanted vagus nerve stimulator, activating anotherneuromodulator, activating an implanted drug pump, begin taking one ormore medications, stop taking medications, increase or reduce medicationdosage, change medication dosing regimen, and other initiation ofaction, change of behavior, or cessation of activity.

In addition to or as an alternative to the output that is indicative ofthe appropriate action, the systems of the present invention may providea variety of other types of outputs to the patient via the patientcommunication assembly 18. While preferred embodiments provide acommunication output to the patient that is indicative of an appropriateaction for the patient to take, it may be desirable to merely providethe patient with different warnings that are indicative of the patient'spropensity for a seizure or the neural state index. For example, asshown in FIG. 11, it may be desirable to simply display the patient'sneural state index 112 that is characterized by the predictivealgorithm. The patient's neural state index is preferably displayed in asimplified scalar form and is updated substantially in real time, but adelay may be acceptable, as long as the delay is shorter than thepredicted time horizon for the seizure.

While not as straight forward as an instruction to the patient, overtime the patient will begin to understand and correlate the neural stateinformation to their particular condition, and the patient will be ableto determine or fine tune the appropriate treatment on their own. Forexample, a patient may know that anytime they have a headache or aspecific taste in their mouth and their neural state index stays atlevel “8” for more than five minutes that a seizure will likely occursometime that day. Consequently, the patient will know to take anappropriate medication or actuate some sort of treatment to manage orcurtail the impending seizure. Furthermore, if the patient's neuralstate indicates an increased propensity for a seizure, but the patientknows that the neural state measurement may have been affected becausethe patient hasn't been sleeping or has recently taken an agent that mayaffect the neural state (e.g., medication, alcohol, etc.), based on thepatient's past experiences, the patient may be able to recognize whetheror not they actually have an increased risk of a seizure or not.

FIGS. 12 to 14 illustrate some additional embodiments of the presentinvention that illustrate different communication outputs that may beprovided to the patient. For ease of reference, the instructions to thepatient are not illustrated in the embodiments, but it should beappreciated that the embodiments of FIGS. 12 to 14 may also includeinstructions that are indicative of the appropriate action. Furthermore,while not described in detail below, instead of displaying the neuralstate information as an alphanumeric character on an output display ofthe patient communication assembly 18, the neural state information maybe communicated to the patient via other displays (graphs, pie charts,bar charts, line charts, bar displays, etc.) or through other outputmeans, such as differing patterns of vibrations, lights, beeps, rings,voice, or other analog or digital outputs.

FIG. 12 illustrates an embodiment in which a “target” or desired neuralstate index 114 is shown alongside the patient's measured neural stateindex 116. Similar to a heart rate monitor, which illustrates a targetheart rate and the actual heart rate, this embodiment would allow thepatient to know where their neural state index is relative to theirtarget neural state index (or target neural state index range), andwould allow the patient to take the appropriate action to move thepatient's neural state index toward the target neural state index. Ascan be appreciated, the patient's target neural state index will likelybe pre-determined and programmed into the memory of the system 10 by aclinician and the target neural state will likely vary from patient topatient. Moreover, the target neural state index may vary over time,with such parameters as whether the patient is sleeping or awake, thetype or amount of antiepileptic drug or other medication the patient ison, or other factors.

As shown in FIG. 13, in another embodiment, it may be useful to merelyshow the difference 118 between the patient's target neural state indexand the patient's measured neural state index. The output may be a+/−“X” over a target range or target neural state index. Depending onthe scalar and the sign of the scalar, the patient should be able todetermine the appropriate action needed (if any). For example, if thepatient's neural state index is within a normal range, the outputprovided to the patient would be “0”. If a large negative number isshown, such a number may indicate that the patient is overmedicated andno more medication should be taken. On the other hand, a small positivenumber may indicate that treatment is needed; if a large positive numberis shown, such a number may indicate that a seizure is imminent and thatthe patient should make themselves safe.

FIG. 14 illustrates an embodiment which is configured to provide avariety of different alert levels 120. Generally, the alert levels arebased at least in part on the measured propensity for seizure or otheroutput provided by the predictive algorithm. For example, while thepropensity for seizure characterizations of the present invention may besimplified down to a scalar between 1-100 (or any other scale), such ascalar may be difficult for some patients to comprehend. To make thingseasier for the patient to understand, system 10 may be configured toprovide for a variety of different “alert levels” that correspond todifferent propensities for seizure. The patient communication assembly18 will be capable of producing outputs that correspond to the alertlevels.

For example, a patient's propensity for a seizure or neural state indexthat is below a lower threshold could be indicative of some degree ofover-medication and could correspond to alert level one and the patientcommunication assembly could display an “over-medicated” output. Apropensity for seizure or neural state index between a lower thresholdand an upper threshold could indicate “normal” or “desired state” andcorrespond to alert level two. A propensity for seizure or neural stateindex above a first upper threshold could indicate mild under-treatmentor mild worsening in the patient's condition, and could correspond toalert level three. Finally, a propensity for seizure or neural stateindex above a second, higher threshold could indicate a severe worseningin the patient's condition (and an imminent seizure), and couldcorrespond to alert level four. The output to the patient may include adisplay on the output display 95 (e.g., alert 1/over-medicated, alert2/normal, alert 3/action needed, or alert 4/immediate action needed),symbols, charts, colors, patterns of sounds or vibrations, or acombination thereof.

While the above example provides four different levels, the presentinvention is not limited to four alert levels. Other embodiments of thepresent invention may have as little as two levels (e.g., normal leveland pre-ictal or abnormal level), or any desired number of differentalert levels (e.g., greater than four alert levels).

The patient communication assembly 18 may only allow for viewing one ofthe display types shown in FIGS. 10-14 or the patient may be allowed toselect the type of output that is displayed or otherwise provided by thepatient communication assembly 18. Thus, the patient may be allowed totoggle between the displays illustrated in FIGS. 10-14. For example, asshown in FIGS. 11-14, if some form of the neural state index or alertlevel is displayed to the patient, the patient communication assembly 18may allow the patient to actuate an input 94 to display the treatmentthat corresponds to the displayed neural state or alert level.Typically, actuation of the input 94 would display an instructionsimilar to the display shown in FIG. 10.

For any of the above embodiments, the patient communication assembly 18may be configured to provide a predetermined, variable, or adaptiveoutput that informs the patient of any important changes in thepatient's propensity for a future seizure. Typically, the output to thepatient may be in the form of a predetermined vibration pattern or ringpattern that indicates to the patient that the patient's condition haschanged or that a specific threshold has been crossed. This would allowthe patient to monitor their condition without having to require thepatient to physically look at the display on the patient communicationassembly 18. Additionally, if the situation becomes more critical, thesystem 10 may be configured to cause the implanted device assembly 12 tovibrate or provide some other type of perceptible output. Typically, theoutput is provided with output assembly 35 (FIG. 5).

In addition to providing an output to the patient through patientcommunication assembly 18 that is indicative of the patient's propensityfor a future seizure or recommendation regarding the appropriate action,the system 10 of the present invention may be configured toautomatically deliver a preventative therapy to the patient. As aninitial attempt to prevent a predicted seizure from occurring, thesystem 10 may automatically deliver an electrical stimulation or othertreatment, such as drug infusion, to the patient through an implantedpatient interface assembly 14′. Optionally, a warning may be provided onpatient communication assembly 18 that informs the patient of theelevated propensity for seizure System 10 may be configured to provide awarning communication to the patient that informs the patient thatstimulation is being provided or that an implanted drug pump has beenactivated so that the patient is aware of the situation. As describedabove, the characterized propensity for the future seizure, may be usedto determine the parameters of the electrical stimulation, drug therapy,or other therapy. Electrical stimulation may be provided substantiallycontinuously in an open-looped fashion or it may be used acutely in aclosed-loop fashion to maintain the patient's propensity for seizure ina desirable range. Suitable systems for generating an electricalstimulation therapy based on a measured state of the patient aredescribed in commonly owned U.S. Pat. Nos. 6,366,813 and 6,819,956.

The present invention may also be used for evaluating pharmacologicalagents and for selecting appropriate pharmacological agents for managingor treating the patient's neurological disorder (e.g., epilepsy).Generally, the methods of the present invention will use the predictivealgorithm 60 described above, but other conventional or proprietarymeans to monitor a patient's neural state and measure the responsivenessof the neural state to the pharmacological agent (or electricalstimulation) may also be used. By changing (1) the drug or drug classused as the pharmacological agent, (2) the form of the pharmacologicalagent (e.g., aerosol, pill, suppository, injection, sub-lingual, liquid,skin cream, or the like), and/or (3) the dosage of the pharmacologicalagent and monitoring the patient's neural state a clinician may be ableto better evaluate the effectiveness of an acute dosage of apharmacological agent relative to the patient's neural state, anddetermine the appropriate type, form, dosage, and timing ofpharmacological agent for managing the patient's neurological disorder.Thus, using the present invention it may be possible to reduce thefrequency and/or dosage of agent so that the patient is taking a reducedamount of the agent and is only taking the pharmacological agent when itis actually needed.

This invention creates a new usage and indication for several classes ofdrugs. Using the systems taught in the present invention, a patient maytake a medication in a preventative manner, rather than on a chronicbasis or on an acute basis to terminate a seizure after it has begun.This seizure preventative indication is a new use of pharmacologicalagents in and of itself. Furthermore, some of the dosing regimens usesignificantly less medication than the dosing used for acute seizuretermination indications, such as is used for terminating repetitiveseizures or status epilepticus.

Neural state may be altered by the administration of chronic and acuteantiepileptic drugs, thereby providing a measure of degree of therapyand response to therapy. The monitored neural state is perturbed bytherapy, further validating the neural state, and providing a measure oftherapy and more specifically of the neural response to therapy. Thiscan be used to titrate therapy as well as to provide real-time feedbackon the response to therapy and real-time estimation of the efficacy oftherapy. The uses of the present invention are multiple, includingtitration of chronic medications, dosing of acute therapy, andmonitoring of response to chronic and acute therapy.

FIG. 15 illustrates one simplified method encompassed by the presentinvention, as applied to the selection and titration of pharmacologicalagents or other therapies in a patient-specific manner. Such a methodallows for the monitoring of a “baseline” neural state, in the absenceof a specific therapy or of all therapies, and the response to theaddition and/or subtraction of specific therapies.

At step 200, the patient's neural state is monitored for a suitableamount of time to ascertain a patient's “baseline” neural state so as toallow for assessment of the effect that the pharmacological agent has onthe patient's neural state. Monitoring of the patient's neural state maybe performed in-hospital or out-of-hospital. This in-hospital “baseline”monitoring may be performed in a variety of settings including but notlimited to in an epilepsy monitoring unit (EMU), an intensive care unit(ICU), or a regular hospital floor bed. Alternatively, this “Baseline”neural state can be measured in a clinic or in an unconstrained mannerusing an ambulatory unit, which may be implanted, non-implanted, or ahybrid. The “Baseline” neural state may be calculated using signalsobtained from scalp electrodes, implanted electrodes, other electrodes,or a combination thereof. The practical durations for monitoring willvary as a function of the method employed. These ranges include up toseveral hours or more in a clinic or hospital setting, hours to severalweeks in an epilepsy monitoring unit (EMU) or other hospital setting, orhours to months using an ambulatory monitoring system. In any of theseor other settings, one may also continue monitoring during the washoutor withdrawal of a drug as well as before, during and following theadministration of the drug. Neural state monitoring may be performedusing any of the embodiments of system 10 described herein or it may bemonitored using other invasive or non-invasive conventional orproprietary systems.

At step 202, the patient is instructed to take one or morepharmacological agents in a first specified dosage. Instructions to takethe pharmacological agent may be carried out by having the patientfollow a clinician defined regimen (e.g., at 12 noon take “X” amount ofpharmacological agent “A”, and at 8 pm take “Y” amount ofpharmacological agent “B”) which may be stored in a memory of system 10and communicated to the patient through the patient communicationassembly 18. This regimen may be predefined or it may be dynamicallyadjusted or a combination of these. For example, certain therapies havea more pronounced effect during specific neural states or rangesthereof; so the timing of therapies may be adjusted to be given duringcertain neural states and the dosing may be a function of the current,historical, or predicted future neural states. Of course, the cliniciandefined regimen may be communicated to the patient in a variety of othermethods, and the present invention is not limited to using system 10 toprovide instructions to the patient.

At step 204, the patient's neural state is monitored to ascertain theperturbation (if any) of the patient's neural state caused by the firstspecified dosage of the pharmacological agent. The effect of thepharmacological agent on the neural state may be ascertained usingsystem identification methods known in the art of control theory anddynamic system modeling. Depending on the route of administration andthe time course of the drug plasma level changes, the perturbation couldbe modeled as a step, impulse, first order, second order, or higherorder process; and the neural state response can be deconvolved with orotherwise analyzed as a response to the drug administration. In thismodel, the administration of the pharmacological agent is the inputfunction or driving function being input into the system, which is thepatient; and the neural state can be viewed as the state or the outputfunction. The transformation from input function to output functionrepresents the neural state response to the administered pharmacologicalagent.

Perturbation caused by the pharmacological agent may take a variety offorms. For example, depending on what the neural state measures, thepharmacological agent may increase some or all elements of the patient'sneural state, decrease some or all elements of the patient's neuralstate, stabilize some or all elements of the patient's neural state, actto reduce or stop a trending of some or all elements of the patient'sneural state, act to maintain a trending of some or all elements of thepatient's neural state, or the like. One response to antiepilepticpharmacological agents causes a transient increase in neural state, asthe various patterns of neural activity become desynchronized inresponse to the medication. At least one of the elements of the neuralstate increases transiently with a time course similar to that of thedrug plasma levels. Some responses are predominantly transient andreturn toward baseline as the drug redistributes, is metabolized, or isexcreted. Other responses are more stable and exhibit a change thatpersists for a longer time period, beyond the increase in plasma levelof the drug. A combination of such neural states, which can be viewed asa vector, can provide a richer level of information characterizing theneural state and its response to therapy than a single scalar neuralstate element does.

Parameters of the neural state responses include the time course ofresponse, time constant of response, magnitude of increase in neuralstate, magnitude of decrease in neural state, degree of stabilization ofneural state, latency of onset of response in neural state, slope orfirst time derivative of change in neural state, other time derivativesof the response in neural state, area under the curve of the neuralstate response, or other features or combinations thereof. The dosage,type, and time of administration of the pharmacological agent and neuralstate response may thereafter be stored in a memory for future analysisby the clinician (step 206).

If a desired number of variations of pharmacological agents have beentested, then the method moves to step 210 (described below). However, ifadditional pharmacological agents need to be tested, at some desiredtime after taking the first specified dosage of the pharmacologicalagent, the patient may be (1) instructed to take the samepharmacological agent in which some parameter (dosage, form, etc.) ofthe agent is varied or (2) instructed to take a different type ofpharmacological agent (step 208, step 202). The different types mayinclude variations in drug class, drug (or agent), drug form (such asintravenous, intramuscular, intranasal, sublingual, buccal, transdermal,intrathecal, intraventricular, intraparenchymal, cortical, oral, rectal,or other formulation or route), or dosages. For example, if there aredifferent forms of the pharmacological agent, such as an aerosol, pill,suppository, injection, sub-lingual, liquid skin cream, transdermalpatch, or the like, the form of the agent may be varied to determine ifthere are different neural state responses to the different forms of theagent.

For each of the additional pharmacological agents administered, thepatient's neural state is again monitored to ascertain the perturbation(if any) of the patient's neural state caused by the second dosage andthe data is stored in memory (Steps 204, 206). The steps are repeateduntil a desired number of different pharmacological agents have beentested.

While not illustrated in FIG. 15, it may be desirable to determine ifthe perturbation effect of the pharmacological agent is substantiallythe same for the patient's different neural states. For example, apharmacological agent may be more effective when the patient is in oneneural state range, but less effective when the patient is in anotherneural state range. The effectiveness of a pharmacological agent mayvary as a function of neural state, becoming progressively moreeffective as a neural state varies along a range. Thus, it may be usefulto instruct the patient to take the same dosage of the samepharmacological agent when the patient is in various a neural stateranges to ascertain the variation, if any, in efficacy of thepharmacological agent. This would allow the clinician to determine ifthere is a different neural response to the same dosage of the samepharmacological agent for the different neural states, and thus allowthe clinician to customize the prescribed pharmacological regimenaccordingly.

For example, as shown in FIG. 16, if the patient's neural state is in arange between 219 and 220 and the patient takes a dosage of a specificAED, the patient's neural state may be perturbed a large amount (or asmall amount, depending on the patient and the AED taken). However, ifthe patient's neural state is within a “normal range” (between lowerthreshold 220 and upper threshold 222) and the patient takes the samedosage of the same pharmacological agent (AED Intake #2), the neuralstate may be perturbed upward a different amount and may take longer forthe perturbation to occur (which in this example, is a lesser amount ina longer period of time). Finally, if the patient's neural state isabove upper threshold 222, the same dosage of the pharmacological agentmay actually have an even lower perturbation effect (or no perturbationeffect) on the neural state. Consequently, it may be desirable to testthe effect of the pharmacological agent have on the neural state whenthe patient is in different neural states to better assess the effectthat the pharmacological agent has on various neural state.

Once the desired number of types, forms and dosages of pharmacologicalagents are tested, the clinician may then analyze the stored data todetermine which type, form, and/or dosage of pharmacological agents areeffective at managing the different neural states of the patient (Step210). For example, some pharmacological agents may act faster, cause alarger perturbation in the neural state, or the like. The clinician mayuse the stored data, alone or in combination with other extrinsic data,to generate a treatment regimen for the patient and program system 10 toprovide specific recommendations for a desired number of patient states.Typically, however, one or more pharmacological agent data (e.g., type,form, dosage, and timing) are programmed into a memory of system 10 andassociated with selected neural states (step 212).

Of course, the treatment regimen will typically include othernon-pharmacological treatments for managing the patient's neural stateand propensity for the future seizure, e.g., electrical stimulation,behavioral modification including making themselves safe, etc., asdescribed above. The treatment regimen may be graded as a function ofneural state, with increasing efficacy, magnitude, or with increasinglytolerated side effects, as the propensity of a seizure increases or asthe seizure prediction horizon decreases. This may involve initialtherapy with vagus nerve stimulation, potentially followed by otherstimulation, and followed with pharmacological intervention, again alonga varying scale. Pharmacotherapy may start with a small dose of aminimally sedating and well tolerated agent and as the time until thepredicted seizure horizon decreases and/or the propensity for seizureincreases, then a series of medication may be administered withprogressively increasing degrees of invasiveness (i.e. oral, sublingual,intranasal, intramuscular, then intravenous) and/or side effects(increasingly sedating).

Referring again to FIG. 15, once system 10 has been properly programmedto specify an appropriate action for specific neural states, system 10may be used on a day-to-day basis to monitor the patient's neural state.As described above, when the patient's neural state reaches one of thespecified neural state thresholds or ranges associated with theclinician defined pharmacological regimen, a communication will beoutput to the patient that is indicative of an appropriate action forthe patient (step 214). Preferably, the appropriate action is in theform of an instruction that indicates the pharmacological treatment thatwas previously determined by the clinician. Typically, the output is inthe form of an instruction or recommendation which specifies at leastone of a type, form, formulation, dosage, and route of administration ofa pharmacological agent. However, it may be helpful to merely indicateto the patient that their risk of a seizure has increased. In the otherend of the spectrum, when the seizure is imminent and prevention of theseizure using a pharmacological agent or other treatment means isunlikely, the communication to the patient may indicate to the patientto put themselves in a safe place. Any combination of instructions,warning, and information is possible.

The patient's reaction to the pharmacological agents may change overtime. Consequently, during regular checkups or through periodicuploading of the patient's neural state information, drug compliancedata, seizure prediction data uploads to the clinician, the clinicianmay be able to monitor the perturbation effect of the pharmacologicalagents on the patient's neural state. If the clinician (or the system 10itself) determines that the programmed pharmacological agent is notachieving the desired result, the clinician will have the ability toprescribe a different pharmacological agent, dosing regimen, or dosageand reprogram the device assembly 12.

While FIGS. 15 and 16 illustrate a method for improving apharmacological regimen for treating epilepsy, such methods may also beused to improve treatments for other neurological disorders andnon-neurological disorders. For example, it may be possible to monitorthe neural state response to medications used in the treatment of otherneurological disorders and improve the medication/pharmacological agentregimen by monitoring the responsiveness to different dosages of thepharmacological agent.

The present invention may also be used for patient screening andresponder selection. By assessing in which patient's the neural state isfound to respond to and by which amount to any of various therapies, onecan assess the relative efficacy of the use of therapies for thatparticular patient. Assessing the response of a patient to vagus nervestimulation, intracranial stimulation, tactile stimulation,pharmacological intervention, or any other therapy, in a preoperativemanner, one can assess the potential efficacy of the present inventionprior to the implantation of an implanted implementation. This hasenormous value in reducing the number of non-responder patients in whoma device may be implanted, improving efficacy and reducing morbidity inpatient who may not benefit from the technology. The degree ofresponsiveness or efficacy may be assessed by the magnitude, latency,time course, and other parameters that may be extracted or calculatedfrom the response in neural state to the administration of therapy tothe patient.

The present invention further provides system and methods that may beused to modify or alter the scheduling and dosing of a chronicallyprescribed pharmacological agent, such as an AED. While the presentinvention is preferably used with acute or non-chronic drug regimens formanaging epilepsy, the systems of the present invention may also be usedwith chronic drug regimens. However, with the present invention, it maybe possible to reduce the dosage or frequency of the chronically takenmedications. The predictive algorithms described above may be still beused to characterize the patient's propensity for the future seizure,typically by monitoring the patient's neural state. If the predictivealgorithm determines that the patient has an increased risk of,propensity for, or probability of an epileptic seizure or otherwisepredicts the onset of a seizure, the system may provide an output thatindicates or otherwise recommends or instructs the patient to take anaccelerated or increased dosage of the chronically prescribedpharmacological agent. Consequently, the present invention is able tomodulate and titrate the intake of the prescribed agent in order todecrease side effects and maximize benefit of the AED. In suchembodiments, it may be possible to maintain a lower plasma level of theAED in the patient, and increase the plasma level of the AED only whenneeded. This allows for maximization of efficacy concurrent withminimization of total medication dose.

In another aspect, the present invention provides systems and methodsfor improving a patient's compliance with a prescribed pharmacologicalregimen and for providing safeguards for controlling the patient'spharmacological agent (e.g., medication) intake. Patient communicationassembly 18 may be programmed to periodically transmit a communicationto the patient when a medication is scheduled to be taken by thepatient. The communication might be carried out via an audio signal(e.g., beep(s), voice, etc.), vibratory signal, visual signal (e.g.,text or graphics provided on a display on patient communication assembly18, flashing lights), other signals, or a combination thereof. In someembodiments, it may be desirable to require the patient to activate aninput device 94 on patient communication assembly 18 every time thepatient takes the medication. Activation of the input signal may carryout a variety of functions. First, it may be used to turn off the“reminder” communication provided by the patient communication assembly18. Second, it may provide an indication to system 10 that themedication has been taken. The input from the patient may be saved in amemory and the saved data may be used by the clinician to assess whetheror not the patient is properly taking their prescribed pharmacologicalagents.

System 10 may also be used to monitor the patient's compliance with theprescribed pharmacological agent regimen. For example, if patientcommunication assembly 18 communicates a signal to the patient to take apharmacological agent and the patient activates the input, but does notactually take the prescribed pharmacological agent, the system may havea compliance component that tracks the patient's input and monitors thepatient's propensity for the future seizure (e.g., neural state) todetermine the patient's response to the pharmacological agent. If noperturbation of the patient's propensity for a seizure is measured or ifthe expected perturbation is not measured within a predetermined timeperiod, the patient communication assembly may generate a secondreminder signal to the patient reminding the patient to take thescheduled pharmacological agent. This can monitor for both noncomplianceand for inadequate response to therapy.

The systems of the present invention may also have safeguards thatmonitor the patient's intake of a pharmacological agent. For example, inone embodiment a maximum threshold of medication over a period of timemay be set by the clinician, and the maximum threshold may be saved in amemory of system 10. As the patient's propensity for the future seizure(e.g., neural state) is monitored, the dosage and time data for thecommunications to the patient which indicate taking the pharmacologicalagent (e.g., medication), may be saved into memory. If the maximumthreshold of medication is reached for the predetermined period of time(e.g., day, week, month, year, or other predetermined time period),system 10 will be prevented from communicating an instruction to thepatient to take additional dosages of the prescribed pharmacologicalinformation. Instead of providing the instruction, system 10 may beconfigured to provide a warning to the patient to indicate that themaximum amount of medication is being reached. Such a warning wouldallow the patient to contact their clinician or the like. In such cases,it may be desirable to have the clinician program a second, alternativepharmacological agent or other appropriate action into memory that wouldthen be output to the patient.

It may be possible to configure system 10 so that when the amount ofmedication taken approaches the maximum, a signal may be sent to aserver that the clinician may access or directly to a cliniciancommunication assembly 20 that is in communication with system 10 thatwarns the clinician of the patient's status. In some embodiments, system10 may be configured to regularly communicate pharmacological agentupdates and/or neural state updates (e.g., number of seizures) to theclinician. This has considerable value in assessing and preventing theoccurrence of an overdose of antiepileptic and other drugs, includingbenzodiazepines or barbiturates.

The present invention may also be used as a seizure monitoring system.Since the system monitors the neural state of the patient and maypredict the onset of a seizure, the system may also be able to determineif a seizure is occurring or has occurred in a patient, the number ofseizures, the time of the seizure, length of the seizure, etc. Such datamay be stored in memory for later assessment by the clinician or forhelping the system 10 adapt to the patient. If a seizure is detected,system 10 may be configured to automatically deliver a predetermined oradaptive electrical stimulation and/or drug infusion in an attempt toabort the seizure or otherwise reduce the magnitude and/or duration ofthe seizure. Additionally, it may be desirable to provide an output tothe patient that informs the patient that a seizure has occurred. Aseizure log may be stored in memory for reference to the clinician andpatient. The systems 10 of the present invention may be used as anout-of hospital monitoring system, and would allow the patient to goabout their day-to-day activities, without being confined to an epilepsymonitoring unit (EMU) in the hospital. The present invention may augmentor replace much of the monitoring performed in an epilepsy monitoringunit (EMU), enabling clinicians to collect long duration blocks ofextracranial or intracranial data from a patient in an ambulatorysetting, depending on the placement of the recording electrodes. Thisallows the clinician to assess the patient's symptoms and neural statein real-life conditions, including variations in plasma levels ofmedications and various environmental influences.

Referring now to FIG. 17, the present invention will further comprisekits 300 including any combination of the components described above,instructions for use (IFU) 302, and packages 304. Typically, the kit 300will include some combination of the device assembly 12, one or morepatient interface assemblies 14, 14′ and patient communication assembly18. The IFU 302 will set forth any of the methods described above.Package 304 may be any conventional medical device packaging, includingpouches, trays, boxes, tubes, or the like. The instructions for use 302will usually be printed on a separate piece of paper, but may also beprinted in whole or in part on a portion of the packaging 304.

Drugs Used in the Treatment of Epilepsy

Some of the AEDs that may be used with the present invention will now bedescribed. The anti-epileptic drugs used of epilepsy fall into threemajor categories. One class of epileptic drugs limits the sustained,repetitive firing of a neuron by promoting the inactivated state ofvoltage-activated Na⁺ channels. Another mechanism is by the enhancementof gamma-aminobutyric acid (GABA)-mediated synaptic inhibition, eitherpre- or post-synaptically. Yet another class of compounds limitactivation of a particular voltage-activated Ca²⁺ channel known as the Tcurrent.

Antiepileptic drugs function by at least one of several mechanisms tocontrol neural firing activity. The major classes based on the mechanismof action are as follows:

1) Modulation of Voltage Dependent Ion Channels

-   -   a) Sodium channel blockade    -   b) Calcium channel blockade    -   c) Potassium channel facilitation

2) Enhancement of Synaptic Inhibition

-   -   a) GABA Agonists        -   i) Benzodiazepines        -   ii) Barbiturates        -   iii) Felbamate        -   iv) Topiramate    -   b) Glycine    -   c) Regionally Specific Transmitter Systems        -   i) Monoamines            -   (1) Catecholamines            -   (2) Serotonin            -   (3) Histamine        -   ii) Neuropeptides            -   (1) Opioid Peptides            -   (2) Neuropeptide Y        -   iii) Inhibitory Neuromodulator    -   (1) Adenosine

3) Inhibition of Synaptic Transmission

-   -   a) NMDA Antagonists    -   b) AMPA Antagonists    -   c) Metabotropic Type    -   d) Kainate Type

Some specific examples of anti-epileptic drugs that may be used with thepresent invention are described below:

Hydantoins:

Phenytoin (diphenylhydantoin, Dilantin, Diphenylan) is used typicallyfor all types of partial and tonic-clonic seizures. Other suitablehydnatoins include mephenytoin, ethotoin.

Phenytoin has the following structure:

A 5-phenyl or other aromatic substituent appears important for activity.Chronic control of seizures is generally obtained with concentrationsabove 10 μg/ml, while toxic effects such as nystagmus develop atconcentrations around 20 μg/ml.Anti-Seizure Barbiturates:

Phenobarbital, N-methylphenobarbital, and metharbital are typically usedin therapies for epilepsy. Other barbituates may also be used in thepresent invention. N-methylphenobarbital (Mephobarbital; Mebaral) andphenobarbital are effective agents for generalized tonic-clonic andpartial seizures.

During long term therapy in adults, the plasma concentration ofphenobarbital averages about 10 μg/ml per daily dose of 1 mg/kg; inchildren the value is between about 5 to about 7 μg/ml per 1 mg/kg.Plasma concentrations of about 10 to about 35 μg/ml are recommended forcontrol of seizures; about 15 μg/ml is generally the minimum forprophylaxis against febrile convulsions.

Deoxybarbiturates:

Primidone (mysoline) is used against partial and tonic-clonic seizures.During long term therapy, plasma concentrations of primidone andphenobarbital average between about 1 μg/ml and about 2 μg/ml,respectively, per daily dose of 1 mg/kg of primidone.

Iminostilbenes:

Carbamazepine is used in the treatment of partial and tonic-clonicseizures. Carbamazepine is a derivative of iminostilbene with a carbamylgroup at the 5 position. Therapeutic concentrations are between about 6to about 12 μg/ml. Oxcarbazepine (Trileptal) is a keto analog ofcarbamazepine which acts as a prodrug in humans. Oxcarbazepine istypically used as a monotherapy or adjunct therapy for partial seizuresin adults and as adjunctive therapy for partial seizures in children.Oxcarbazepine is thought to block voltage-sensitive sodium channels. Inaddition, increases potassium conductance and modulation of high-voltageactivated calcium channels, which may also have a role in controllingseizures. Dosage is between about 0.6 to about 2.4 g/day.

Succinimides:

Ethosuximide (Zarontin) is typically used for the treatment of absenceseizures. Methsuximide (Celontin) and phensuximide (Milontin) havephenyl substituents and are more active against maximal electroshockseizures. During long-term therapy, the plasma concentration ofethosuximide averages between about 2 μg/ml per daily dose of 1 mg/kg. Aplasma concentration of between about 40 to about 400 μg/ml is requiredfor satisfactory control of absence seizures in most patients. Aninitial daily dose of 250 mg in children and 500 mg in older childrenand adults is increased by 250 mg increments at weekly intervals untilseizures are adequately controlled or toxicity intervenes. Divideddosage is required occasionally to prevent nausea or drowsinessassociated with single daily dosage. The usual maintenance dose is about20 mg/kg per day.

Valproic Acid:

Valproic acid (n-dipropylacetic acid) is a simple branched-chaincarboxylic acid. The concentration of valproate in plasma that isassociated with therapeutic effects is between about 30 to about 100μg/ml. Valproate is effective in the treatment of absence, myoclonic,partial, and tonic-clonic seizures. The initial daily dose is usuallyabout 15 mg/kg, and this is increased at weekly intervals by betweenabout 5 to about 10 mg/kg per day to a maximum daily dose of 6 mg/kg.Divided doses are given when the daily dose exceeds 250 mg.

Benzodiazepines:

A large number of benzodiazepines have broad anti-seizure properties. Inthe United States, clonazepam (Klonopin) and clorazepate (Traxene-SD,others) have been approved for chronic, long term treatment of seizures.Diazepam (Valium, Diastat, others) and lorazepam (Ativa) are commonlyused in the management of status epilepticus.

Clonazepam is useful in the therapy of absence seizures as well asmyoclonic seizures in children. The initial dose of clonazepam foradults does not typically exceed 1.5 mg per day, and for children isbetween about 0.01 to about 0.03 mg/kg per day. The dose-dependent sideeffects are reduced if two or three divided doses are given each day.The dose may be increased every 3 days in amounts of between about 0.25to about 0.5 mg per day in children and between about 0.5 to about 1 mgper day in adults. The maximal recommended does is 20 mg per day foradults and 0.2 mg/kg per day for children.

While diazepam is an effective agent for treatment of statusepilepticus, its short duration of action is a disadvantage, leading tothe use of intravenous phenytoin in combination with diazepam. Diazepamis administered intravenously and at a rate of no more than about 5 mgper minute. The usual dose for adults is between about 5 to about 10 mgas required; this may be repeated at intervals of 10 to 15 minutes, upto a maximal dose of about 30 mg. If necessary, this regime can berepeated in 2 to 4 hours, but no than 100 mg should be administered in a24-hour period.

Clorazepate is effective in combination with certain other drugs in thetreatment of partial seizures. The maximum initial dose of clorazepateis 22.5 mg per day in three portions for adults and 15 mg per day in twodoses in children.

Gabapentin:

Gabapentin (Neurontin) is typically used in the treatment of partialseizures, with and without secondary generalization, in adults when usedin addition to other anti-seizure drugs. Gabapentin is usually effectivein doses of between about 900 to about 1800 mg daily in three doses.Therapy is usually begun with a low dose (300 mg once on the first day),and the dose is increased in daily increments of 300 mg until aneffective dose is reached. Gabapentin is structurally related to theneurotransmitter, GABA.

Lamotrigine:

Lamotrigine (Lamictal) is a phenyltriazine derivative. It is used formonotherapy and add-on therapy of partial and secondarily generalizedtonic-clonic seizures in adults and Lennox-Gastaut syndrome in bothchildren and adults. Patients who are already taking a hepaticenzyme-inducing anti-seizure drug are typically given lamotrigineinitially at about 50 mg per day for 2 weeks. The dose is increased toabout 50 mg twice per day for 2 weeks and then increased in incrementsof about 100 mg/day each week up to a maintenance dose of between about300 to about 500 mg/day in two divided doses. For patients takingvalproate in addition to an enzyme-inducing anti-seizure drug, theinitial dose is typically about 25 mg every other day for 2 weeks,followed by an increase to 25 mg/day for two weeks; the dose then can beincreased to 50 mg/day every 1 to 2 weeks up to a maintenance dose ofabout 100 to about 150 mg/day divided into two doses. Lamotrigine is ause-dependent blocker of voltage-gated sodium channels and inhibitor ofglutamate release.

Levetiracetam:

Levetiracetam (Keppra) is a pyrrolidine, the racemically pureS-enantiomer of α-ethyl-2-oxo-1-pyrrolidineacetamide, and is typicallyused for treating partial seizures. Dosage is about 3 gm/day.

Tiagabine:

Tiagabine inhibits the uptake of the neurotransmitter GABA, whichresults in an increase in GABA-mediated inhibition with in the brain.The dosage with enzyme-inducing drugs is between about 30 to about 45mg/day and without enzyme-inducing drugs is between about 15 to about 30mg/day.

Topiramate:

Topiramate is a sulphamate-substituted monosaccharide. Its mode ofaction probably involves the following: blockade of voltage-sensitivesodium channels; enhancement of GABA activity; antagonism of certainsubtypes of glutamate receptors; and inhibition of some isozymes ofcarbonic anhydrase. The dosage is between about 200 to about 400 mg/day,with a maximum of about 800 mg/day.

Zonisamide:

ZONEGRAN™ (zonisamide) is an anti-seizure drug chemically classified asa sulfonamide. The active ingredient is zonisamide,1,2-benzisoxazole-3-methanesulfonamide. ZONEGRAN is supplied for oraladministration as capsules containing 100 mg zonisamide.

Zonisamide may produce these effects through action at sodium andcalcium channels. In vitro pharmacological studies suggest thatzonisamide blocks sodium channels and reduces voltage-dependent,transient inward currents (T-type Ca²⁺ currents), consequentlystabilizing neuronal membranes and suppressing neuronalhypersynchronization. In vitro binding studies have demonstrated thatzonisamide binds to the GABA/benzodiazepine receptor ionophore complexin an allosteric fashion which does not produce changes in chlorideflux. Other in vitro studies have demonstrated that zonisamide (10-30μg/mL) suppresses synaptically-driven electrical activity withoutaffecting postsynaptic GABA or glutamate responses (cultured mousespinal cord neurons) or neuronal or glial uptake of [3H]-GABA (rathippocampal slices). Thus, zonisamide does not appear to potentiate thesynaptic activity of GABA. In vivo microdialysis studies demonstratedthat zonisamide facilitates both dopaminergic and serotonergicneurotransmission. Zonisamide also has weak carbonic anhydraseinhibiting activity, but this pharmacologic effect is not thought to bea major contributing factor in the antiseizure activity of zonisamide.

ZONEGRAN (zonisamide) is recommended as adjunctive therapy for thetreatment of partial seizures in adults. ZONEGRAN is administered onceor twice daily, except for the daily dose of 100 mg at the initiation oftherapy. ZONEGRAN is given orally and can be taken with or without food.The initial dose is 100 mg daily. After two weeks, the dose may beincreased to 200 mg/day for at least two weeks. It can be increased to300 mg/day and 400 mg/day, with the dose stable for at least two weeksto achieve steady state at each level. Evidence from controlled trialssuggests that ZONEGRAN doses of 100-600 mg/day are effective.

Vigabatrin:

Vigabatrin is an irreversible inhibitor of gamma-aminobutyric acidtransaminase (GABA-T), the enzyme responsible for the catabolism of theinhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain.The mechanism of action of vigabatrin is attributed to irreversibleenzyme inhibition of GABA-T, and consequent increased levels of theinhibitory neurotransmitter, GABA. The dosage is between about 2 toabout 3 g/day, with a maximum of about 3 g/day.

The recommended starting dose is 1 g/day, although patients with severeseizure manifestations may require a starting dose of up to 2 g/day. Thedaily dose may be increased or decreased in increments of 0.5 gdepending on clinical response and tolerability. The optimal dose rangeis between about 2 to about 4 g/day. Increasing the dose beyond 4 g/daydoes not usually result in improved efficacy and may increase theoccurrence of adverse reactions. The recommended starting dose inchildren is 40 mg/kg/day, increasing to about 80 to about 100 mg/kg/day,depending on response. Therapy may be started at about 0.5 g/day, andraised by increments of about 0.5 g/day weekly, depending on clinicalresponse and tolerability.

Methods of Use of the Anti-Epileptic Drugs

Current antiepileptic drugs (AEDs) are used to treat one of twoindications: (1) to reduce the frequency of seizures, and (2) toterminate seizures once they have begun. For the first indication,antiepileptic drugs designed to have a long half life are dosed tomaintain a desired level of a blood plasma concentration of the drug. Bymaintaining stable blood plasma concentrations of the AEDs, the seizurethreshold is increased and the frequency of seizures that occur isusually reduced. This is an “open-loop” approach to therapy, in whichtherapy is stable and is not adjusted in response to any changes in thepatient's propensity for a seizure. An example is the use of phenytoin(Dilantin), which is given preferably once every 8 hours, but whose halflife is long enough to permit once daily dosing in less compliant orcapable patents.

For the second indication, AEDs are used to terminate a seizure after ithas begun and has become clinically evident. In these indications, theseizure has already generalized, and the patient is typicallyincapacitated. Another person, either a family member or medicalcaregiver, administers a medication to terminate the seizure. Examplesinclude (A) rectal diazepam (diastat) which may be given by familymembers or medical personnel and (B) intravenous lorazepam, which istypically given once a patient has been admitted to the hospital fortreatment.

The methods taught in the present invention provide novel approaches tothe treatment of epilepsy. In one aspect of the invention, rather thanprovide chronic, continuous levels of medication which are unchangeddespite changes in the patient's propensity for the seizure or waituntil a seizure has incapacitated the patient, the present inventionteaches the acute, preventative delivery of a pharmacological agent,preferably an anti-epileptic drug, that can modulate the patient'spropensity for the seizure and prevent the further progression into astate that facilitates or predisposes to a seizure state. In oneembodiment of the invention, the dosing and administration of ananti-epileptic drug is co-related to or a function of the patient'spropensity for the future seizure, this characterization typically beingrelated to the measured neural state, or the like. In another embodimentof the invention, the dosing and administration of an anti-epilepticdrug is co-related to or a function of a probability and/or a predictedtime horizon that a patient has before the epileptic seizure ispredicted to occur. Typically, the longer the predicted amount of timeand lower probability, the lower the dose of the epileptic drug, andvice-versa. Also, the route of administration may also vary based on thetiming of the prediction and probability.

In a preferred embodiment, a lower dose of an anti-epileptic drug isadministered to a patient. This dose may be about 5% to about 95% lowerthan the recommended dose for the drug, and preferably at or below 90%of the recommended dose, and most preferably below about 50% of therecommended dose. This lower dose is preferably administered acutely toperturb the patient's neural state and reduce the patient's propensityfor seizures. Tables 1 and 2 provide some examples of dosages of someanti-epileptic drugs and formulation types that can be administered to apatient based on a prediction horizon. The prediction horizon is theamount of time after which the patient could have an epileptic seizureand is directly correlated to the propensity or probability of having aseizure. For example, a one minute prediction horizon means that theprediction algorithm has predicated that the patient is at relativelyhigh propensity for a seizure and will likely have an epileptic seizurein about 1 minute. The column on the left side of the “Drug Dosing”portion of the chart illustrates the conventional “recommended dosage,”and the columns to the right of the “recommended dosage” illustrate someexamples of the potential reduced dosage, based on the predictionhorizon. While not shown in Tables 1 and 2, similar tables could beprovided that are based on the patient's neural state or propensity forseizure. Thus, instead of having the prediction horizon as headings, thecorresponding neural state or propensity for seizure may be used.

TABLE 1 Drug Dosing (mg/kg) - Levels needed if given: Anti-EpilepticDrug After Prediction Horizon (min) (Pediatric Dosing) Seizure Onset 1 510 15 20 25 30 Buccal Midazolam 0.5 0.25 0.125 0.0625 0.03125 0.0156250.007813 0.003906 Intranasal Midazolam 0.2 0.1 0.05 0.025 0.0125 0.006250.003125 0.001563 IM Midazolam 0.2 0.1 0.05 0.025 0.0125 0.006250.003125 0.001563 Rectal Diazepam 0.5 0.25 0.125 0.0625 0.03125 0.0156250.007813 0.003906 IV Lorazepam 0.1 0.05 0.025 0.0125 0.00625 0.0031250.001563 0.000781 IV Diazepam 0.3 0.15 0.075 0.0375 0.01875 0.0093750.004688 0.002344

TABLE 2 Drug Dosing (mg) - Levels needed if given: Anti-Epileptic DrugAfter Prediction Horizon (min) (Adult Dosing) Seizure Onset 1 5 10 15 2025 30 Rectal Diazepam 10 5 2.5 1.25 0.625 0.3125 0.15625 0.078125Lorazepam 4 2 1 0.5 0.25 0.125 0.0625 0.03125 Diazepam 10 5 2.5 1.250.625 0.3125 0.15625 0.078125

The dose administered to the patient is useful to prevent the occurrenceof the future seizures. Preferably, the dose is related to the type ofAED being administered, the type of formulation, and/or thepharmacokinetics of the drug and formulation. FIGS. 21 and 22 giveexamples of drug dosing schedules which compare the drug dosing to theprediction horizon. FIG. 21 provides an example of the doses of buccalmidazolam related to the prediction horizon. FIG. 22 provides an exampleof the various doses for different forms of benzodiazepines. Some othersuitable drugs, doses, and formulations suitable for the presentinvention are provided in Table 3.

TABLE 3 Approximate Dose Compared to (dose Time to Clinical used inseizure Drug Formulation Prediction Horizon Onset Termination) MidazolamBuccal 5 to 30 minutes 5 to 8 minutes 20-30% (0.5 mg/kg) MidazolamIntranasal 1 to 20 minutes 30 sec to 2 minutes 10-25% (0.2 mg/kg)Diazepam Rectal 10 to 30 minutes  5 to 15 minutes 10-25% (0.3 mg/kg)Midazolam Intramuscular 1 to 30 minutes 1 to 5 minutes  5-20% (0.2mg/kg) Midazolam Intravenous 1 to 10 minutes 1 to 5 minutes  5-20% (0.2mg/kg)

Another aspect of the invention is a method for preventing or otherwisemanaging epileptic seizures. One embodiment involves administration ofan effective amount of an anti-epileptic drug to a patient. The acuteadministration may be provided locally to a nervous system component ordelivered systemically to the patient. The acute administration isprovided at a time prior to a possible occurrence of a seizure.Typically, this time is about greater than 30 seconds, and preferablybetween about 1 minute to about 30 minutes. The dose of AED administeredis typically between 5% and 95% lower than a dose of said drug that iseffective after a seizure has occurred, and preferably less than about50% of the drug that is effective after the seizure has occurred. Insome cases, it may be possible to reduce the dosage of the drug to bebetween about 50% and about 5% of the drug that is effective after theseizure has occurred, but depending on the propensity, it may bepossible to reduce the dosage even greater. The amount of AEDadministered may also be a function of the time before a seizure mayoccur. That is, the longer the time before a seizure may occur, thesmaller the dose of the AED administered. This administration istypically an acute administration and could comprise about 2 to about 10doses being administered, preferably all the doses being administeredbefore the occurrence of a seizure.

The dose of drug administered may be greater than or equal to about 100%of the dose normally administered to patients. However, the preferreddose of the AEDs administered herein is a fraction of the normal dose.This normal dose is typically the dose that is considered to be aneffective dose in the art (or by the FDA) to reduce and/or eliminate theoccurrence of a seizure after a seizure has occurred. The dose used inthe invention herein could also be a fraction of the dose that has beenused and has been found effective in a particular patient or asub-population of patients. That is, in some patients it is possiblethat the dose used is higher or lower than the recommended dose, and inthese patients the dose administered is a fraction of the dose that iseffective in reducing and/or eliminating the occurrence of a seizure inthem after a seizure has occurred. The normal dose can be found fordifferent patient populations and/or different kinds of seizures in textbooks, the Physician's Desk Reference, or approved by a regulatoryagency, such as the Food and Drug Administration (FDA). Optionally, thesystem can be utilized with a particular patient or sub-population ofpatients to identify the optimum drug, the appropriate dosage for thatpatient, and/or the dosage that correlates to the prediction horizon orexpected onset of the seizure by evaluating the data from the system andmodifying the treatment accordingly.

Screening for Drugs and Patient Responder Population:

Another aspect of the invention provides methods for screening noveland/or existing anti-epileptic agents for their anti-epilepticproperties for particular patients. The present invention also providesmethods for screening for patient responder subpopulations.

These methods preferably involve characterizing the patient's neuralstate by classifying extracted features from one or more signals fromthe patient, patient history, and patient feedback. For example, theneural state may be monitored before and after administration of a drug,and the effects of the drug the neural state may be used to determinethe efficacy of the drugs. Also, the neural state characterization maybe used to identify patients who potentially will respond to certainAEDs. For example, prior to administering an AED to a patient, thepatient's neural state is characterized. If neural state (as shown byextracted features, such as the STLmax and/or T-index values) aremodulated by the AED so as to indicate a favorable modulation of theneural state, the patient may be considered to be a responder to the AEDbeing tested. Also, this monitoring can be used to study the efficacy ofAEDs in specific patient sub-populations.

One method of characterizing the patient's neural state comprises theanalysis of dynamical characteristics of EEG signals. For example,modulation of specific dynamical conditions may be monitored and itseffect on EEG dynamics is examined to understand the different neuralstates of the patient. In one embodiment, the neural state is at leastpartially characterized by higher values of a T-Index, a measure thatindicates lower dynamical similarity in the EEG signal derived fromelectrodes located over widespread areas of the cerebral cortex.Typically, during an inter-ictal state, the T-index is high.

As is described by U.S. Pat. No. 6,304,775, epileptic seizures aretypically preceded and accompanied by characteristic dynamical changesdetectable in the spatiotemporal patterns of the EEG. In one particularembodiment, in which the neural state is characterized by STL max,seizures are preceded by convergence in the value of STLmax amongspecific EEG electrode sites, beyond that seen normally in theinter-ictal phase. This can be observed by monitoring STLmax values overtime from EEG signals obtained using intracranial or scalp electrodes.In one embodiment, the STLmax values extracted from EEG signals are usedto screen for drugs with anti-epileptic properties and also used toscreen for patient responder subpopulations. The convergence of STLmaxamong critical electrodes can be measured by calculating a T-index, anormalized mean difference of the STLmax between selected electrodes.Thus, prior to a seizure, there has been found to be a decrease in theT-index, more than its normal fluctuation, as the values of STLmaxconverge. In some embodiments, the T-index is used in the screeningmethods described herein.

During a complex partial or secondarily generalized seizure, STLmaxvalues calculated from all electrode sites tend to converge to a commonvalue and fall abruptly in value. The postictal state is characterizedby a gradual increase in the values of STLmax to the valuescharacteristic of the interictal state and a divergence in values amongelectrode sites. This divergence is reflected by a rise in the value ofthe T-index. In another embodiment, these characteristics are used inthe screening methods described herein. Not intending to be limited toone mechanism of action, it is believed that the convergence of STLmaxvalues represents a dynamical entrainment among large areas of theepileptic brain. Further, it is believed that it is this entrainmentthat increases the likelihood of a seizure developing. This suggeststhat an intervention aimed at reducing the convergence, which causes theT-index to increase, could offer a protective effect and decrease thelikelihood of a seizure.

As can be appreciated, while the above example use the T-Index andSTLmax values as extracted features for characterizing neural state, itshould be appreciated that such features are just examples of someuseful features that may be used to characterize the patient's neuralstate, and that any combination of the features described herein and/orother suitable techniques known in the art may be used to characterizethe patient's neural state to screen for drugs and to screen for patientresponder subpopulations.

Dosage, Routes of Administration, and Formulations:

Yet another aspect of the present invention relates to formulations,routes of administration and effective doses for pharmaceuticalcompositions comprising a compound or combination of compounds of theinstant invention. Such pharmaceutical compositions are used in thetreatment, preferably prevention, of epilepsy, as described in detailabove.

In some embodiments, the compounds may be used in combination with oneor more other compounds or with one or more other forms. The two or morecompounds may be formulated together, in the same dosage unit e.g. inone cream, suppository, tablet, capsule, or packet of powder to bedissolved in a beverage; or each compound may be formulated in aseparate unit, e.g., two creams, two suppositories, two tablets, twocapsules, a tablet and a liquid for dissolving the tablet, a packet ofpowder and a liquid for dissolving the powder, etc.

The compounds of the present invention may be administered as apharmaceutically acceptable salt. The term “pharmaceutically acceptablesalt” means those salts which retain the biological effectiveness andproperties of the compounds used in the present invention, and which arenot biologically or otherwise undesirable.

Typical salts are those of the inorganic ions, such as, for example,sodium, potassium, calcium, magnesium ions, and the like. Such saltsinclude salts with inorganic or organic acids, such as hydrochloricacid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid,succinic acid, lactic acid, mandelic acid, malic acid, citric acid,tartaric acid or maleic acid. In addition, if the compound(s) contain acarboxy group or other acidic group, it may be converted into apharmaceutically acceptable addition salt with inorganic or organicbases. Examples of suitable bases include sodium hydroxide, potassiumhydroxide, ammonia, cyclohexylamine, dicyclohexyl-amine, ethanolamine,diethanolamine, triethanolamine, and the like. A pharmaceuticallyacceptable ester or amide refers to those which retain biologicaleffectiveness and properties of the compounds used in the presentinvention, and which are not biologically or otherwise undesirable.Typical esters include ethyl, methyl, isobutyl, ethylene glycol, and thelike. Typical amides include unsubstituted amides, alkyl amides, dialkylamides, and the like.

In some embodiments, a compound may be administered in combination withone or more other compounds, forms, and/or agents, e.g., as describedabove. Pharmaceutical compositions comprising combinations with one ormore other active agents can be formulated to comprise certain molarratios. The two compounds, forms and/or agents may be formulatedtogether, in the same dosage unit e.g. in one cream, suppository,tablet, capsule, or packet of powder to be dissolved in a beverage; oreach compound, form, and/or agent may be formulated in separate units,e.g., two creams, suppositories, tablets, two capsules, a tablet and aliquid for dissolving the tablet, a packet of powder and a liquid fordissolving the powder, etc.

If necessary or desirable, the compounds and/or combinations ofcompounds may be administered with still other agents. The choice ofagents that can be co-administered with the compounds and/orcombinations of compounds of the instant invention can depend, at leastin part, on the condition being treated.

The compound(s) (or pharmaceutically acceptable salts, esters or amidesthereof) may be administered per se or in the form of a pharmaceuticalcomposition wherein the active compound(s) is in an admixture or mixturewith one or more pharmaceutically acceptable carriers. A pharmaceuticalcomposition, as used herein, may be any composition prepared foradministration to a subject. Pharmaceutical compositions for use inaccordance with the present invention may be formulated in conventionalmanner using one or more physiologically acceptable carriers, comprisingexcipients, diluents, and/or auxiliaries, e.g., which facilitateprocessing of the active compounds into preparations that can beadministered. Proper formulation may depend at least in part upon theroute of administration chosen. The compound(s) useful in the presentinvention, or pharmaceutically acceptable salts, esters, or amidesthereof, can be delivered to a patient using a number of routes or modesof administration, including oral, buccal, topical, rectal, transdermal,transmucosal, subcutaneous, intravenous, and intramuscular applications,as well as by inhalation.

For oral administration, the compounds can be formulated readily bycombining the active compound(s) with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds ofthe invention to be formulated as tablets, including chewable tablets,pills, dragees, capsules, lozenges, hard candy, liquids, gels, syrups,slurries, powders, suspensions, elixirs, wafers, and the like, for oralingestion by a patient to be treated. Such formulations can comprisepharmaceutically acceptable carriers including solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents.Generally, the compounds of the invention will be included atconcentration levels ranging from about 0.5%, about 5%, about 10%, about20%, or about 30% to about 50%, about 60%, about 70%, about 80% or about90% by weight of the total composition of oral dosage forms, in anamount sufficient to provide a desired unit of dosage.

Aqueous suspensions for oral use may contain compound(s) of thisinvention with pharmaceutically acceptable excipients, such as asuspending agent (e.g., methyl cellulose), a wetting agent (e.g.,lecithin, lysolecithin and/or a long-chain fatty alcohol), as well ascoloring agents, preservatives, flavoring agents, and the like.

In some embodiments, oils or non-aqueous solvents may be required tobring the compounds into solution, due to, for example, the presence oflarge lipophilic moieties. Alternatively, emulsions, suspensions, orother preparations, for example, liposomal preparations, may be used.With respect to liposomal preparations, any known methods for preparingliposomes for treatment of a condition may be used. See, for example,Bangham et al., J. Mol. Biol. 23: 238-252 (1965) and Szoka et al., Proc.Natl Acad. Sci. USA 75: 4194-4198 (1978), incorporated herein byreference. Ligands may also be attached to the liposomes to direct thesecompositions to particular sites of action. Compounds of this inventionmay also be integrated into foodstuffs, e.g., cream cheese, butter,salad dressing, or ice cream to facilitate solubilization,administration, and/or compliance in certain patient populations.

Pharmaceutical preparations for oral use can be obtained as a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; flavoring elements, cellulose preparations such as, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate. The compounds may alsobe formulated as a sustained release preparation.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compounds.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for administration.

For injection, the compounds of the present invention may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. Such compositions may also include one or more excipients, forexample, preservatives, solubilizers, fillers, lubricants, stabilizers,albumin, and the like. Methods of formulation are known in the art, forexample, as disclosed in Remington's Pharmaceutical Sciences, latestedition, Mack Publishing Co., Easton P.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation or transcutaneous delivery (forexample subcutaneously or intramuscularly), intramuscular injection oruse of a transdermal patch. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

The compositions according to the present invention may be in any formsuitable for topical application, including aqueous, aqueous-alcoholicor oily solutions, lotion or serum dispersions, aqueous, anhydrous oroily gels, emulsions obtained by dispersion of a fatty phase in anaqueous phase (O/W or oil in water) or, conversely, (W/O or water inoil), microemulsions or alternatively microcapsules, microparticles orlipid vesicle dispersions of ionic and/or nonionic type. Thesecompositions can be prepared according to conventional methods. Otherthan the compounds of the invention, the amounts of the variousconstituents of the compositions according to the invention are thoseconventionally used in the art.

In some preferred embodiments, the compounds of the present inventionare delivered in soluble rather than suspension form, which allows formore rapid and quantitative absorption to the sites of action. Ingeneral, formulations such as jellies, creams, lotions, suppositoriesand ointments can provide an area with more extended exposure to thecompounds of the present invention, while formulations in solution,e.g., sprays, provide more immediate, short-term exposure.

In some embodiments relating to topical/local application, thepharmaceutical compositions can include one or more penetrationenhancers. For example, the formulations may comprise suitable solid orgel phase carriers or excipients that increase penetration or helpdelivery of compounds or combinations of compounds of the inventionacross a permeability barrier, e.g., the skin. Many of thesepenetration-enhancing compounds are known in the art of topicalformulation, and include, e.g., water, alcohols (e.g., terpenes likemethanol, ethanol, 2-propanol), sulfoxides (e.g., dimethyl sulfoxide,decylmethyl sulfoxide, tetradecylmethyl sulfoxide), pyrrolidones (e.g.,2-pyrrolidone, N-methyl-2-pyrrolidone, N-(2-hydroxyethyl)pyrrolidone),laurocapram, acetone, dimethylacetamide, dimethylformamide,tetrahydrofurfuryl alcohol, L-α-amino acids, anionic, cationic,amphoteric or nonionic surfactants (e.g., isopropyl myristate and sodiumlauryl sulfate), fatty acids, fatty alcohols (e.g., oleic acid), amines,amides, clofibric acid amides, hexamethylene lauramide, proteolyticenzymes, α-bisabolol, d-limonene, urea and N,N-diethyl-m-toluamide, andthe like Additional examples include humectants (e.g., urea), glycols(e.g., propylene glycol and polyethylene glycol), glycerol monolaurate,alkanes, alkanols, ORGELASE, calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and/or otherpolymers. In some embodiments, the pharmaceutical compositions willinclude one or more such penetration enhancers.

In some embodiments, the pharmaceutical compositions for local/topicalapplication can include one or more antimicrobial preservatives such asquaternary ammonium compounds, organic mercurials, p-hydroxy benzoates,aromatic alcohols, chlorobutanol, and the like.

The compounds may be rectally delivered solutions, suspensions,ointments, enemas and/or suppositories comprising a compound orcombination of compounds of the present invention.

Also the compounds can be delivered effectively with aerosol solutions,suspensions or dry powders comprising a compound or combination ofcompounds of the present invention. The aerosol can be administeredthrough the respiratory system or nasal passages. For example, oneskilled in the art will recognize that a composition of the presentinvention can be suspended or dissolved in an appropriate carrier, e.g.,a pharmaceutically acceptable propellant, and administered directly intothe lungs using a nasal spray or inhalant. For example, an aerosolformulation comprising a compound of the invention can be dissolved,suspended or emulsified in a propellant or a mixture of solvent andpropellant, e.g., for administration as a nasal spray or inhalant.Aerosol formulations may contain any acceptable propellant underpressure, preferably a cosmetically or dermatologically orpharmaceutically acceptable propellant, as conventionally used in theart.

An aerosol formulation for nasal administration is generally an aqueoussolution designed to be administered to the nasal passages in drops orsprays. Nasal solutions can be similar to nasal secretions in that theyare generally isotonic and slightly buffered to maintain a pH of about5.5 to about 6.5, although pH values outside of this range canadditionally be used. Antimicrobial agents or preservatives can also beincluded in the formulation.

An aerosol formulation for inhalations and inhalants can be designed sothat the compound or combination of compounds of the present inventionis carried into the respiratory tree of the subject when administered bythe nasal or oral respiratory route. Inhalation solutions can beadministered, for example, by a nebulizer. Inhalations or insufflations,comprising finely powdered or liquid drugs, can be delivered to therespiratory system as a pharmaceutical aerosol of a solution orsuspension of the compound or combination of compounds in a propellant,e.g., to aid in disbursement. Propellants can be liquefied gases,including halocarbons, for example, fluorocarbons such as fluorinatedchlorinated hydrocarbons, hydrochlorofluorocarbons, andhydrochlorocarbons, as well as hydrocarbons and hydrocarbon ethers.

Halocarbon propellants useful in the present invention includefluorocarbon propellants in which all hydrogens are replaced withfluorine, chlorofluorocarbon propellants in which all hydrogens arereplaced with chlorine and at least one fluorine, hydrogen-containingfluorocarbon propellants, and hydrogen-containing chlorofluorocarbonpropellants. Halocarbon propellants are described in Johnson, U.S. Pat.No. 5,376,359, issued Dec. 27, 1994; Byron et al., U.S. Pat. No.5,190,029, issued Mar. 2, 1993; and Purewal et al., U.S. Pat. No.5,776,434, issued Jul. 7, 1998. Hydrocarbon propellants useful in theinvention include, for example, propane, isobutane, n-butane, pentane,isopentane and neopentane. A blend of hydrocarbons can also be used as apropellant. Ether propellants include, for example, dimethyl ether aswell as the ethers. An aerosol formulation of the invention can alsocomprise more than one propellant. For example, the aerosol formulationcan comprise more than one propellant from the same class, such as twoor more fluorocarbons; or more than one, more than two, more than threepropellants from different classes, such as a fluorohydrocarbon and ahydrocarbon. Pharmaceutical compositions of the present invention canalso be dispensed with a compressed gas, e.g., an inert gas such ascarbon dioxide, nitrous oxide or nitrogen.

Aerosol formulations can also include other components, for example,ethanol, isopropanol, propylene glycol, as well as surfactants or othercomponents such as oils and detergents. These components can serve tostabilize the formulation and/or lubricate valve components.

The aerosol formulation can be packaged under pressure and can beformulated as an aerosol using solutions, suspensions, emulsions,powders and semisolid preparations. For example, a solution aerosolformulation can comprise a solution of a compound of the invention in(substantially) pure propellant or as a mixture of propellant andsolvent. The solvent can be used to dissolve the compound and/or retardthe evaporation of the propellant. Solvents useful in the inventioninclude, for example, water, ethanol and glycols. Any combination ofsuitable solvents can be use, optionally combined with preservatives,antioxidants, and/or other aerosol components.

An aerosol formulation can also be a dispersion or suspension. Asuspension aerosol formulation may comprise a suspension of a compoundor combination of compounds of the instant invention and a dispersingagent. Dispersing agents useful in the invention include, for example,sorbitan trioleate, oleyl alcohol, oleic acid, lecithin and corn oil. Asuspension aerosol formulation can also include lubricants,preservatives, antioxidant, and/or other aerosol components.

An aerosol formulation can similarly be formulated as an emulsion. Anemulsion aerosol formulation can include, for example, an alcohol suchas ethanol, a surfactant, water and a propellant, as well as a compoundor combination of compounds of the invention. The surfactant used can benonionic, anionic or cationic. One example of an emulsion aerosolformulation comprises, for example, ethanol, surfactant, water andpropellant. Another example of an emulsion aerosol formulationcomprises, for example, vegetable oil, glyceryl monostearate andpropane.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are present in aneffective amount, i.e., in an amount effective to achieve therapeuticand/or prophylactic benefit in an epileptic condition. The actual amounteffective for a particular application will depend on the condition orconditions being treated, the condition of the subject, the formulation,and the route of administration, as well as other factors known to thoseof skill in the art. Determination of an effective amount of a compoundis well within the capabilities of those skilled in the art, in light ofthe disclosure herein, and will be determined using routine optimizationtechniques.

The effective amount for use in humans can be determined from animalmodels. For example, a dose for humans can be formulated to achievecirculating, liver, topical and/or gastrointestinal concentrations thathave been found to be effective in animals. One skilled in the art candetermine the effective amount for human use, especially in light of theanimal model experimental data.

The effective amount when referring to a compound or combination ofcompounds of the invention will generally mean the dose ranges, modes ofadministration, formulations, etc., that have been recommended orapproved by any of the various regulatory or advisory organizations inthe medical or pharmaceutical arts (e.g., FDA, AMA) or by themanufacturer or supplier. Effective amounts can be found, for example,in the Physicians Desk Reference.

EXAMPLES

In some embodiments, administration of compounds of the presentinvention may be intermittent, for example administration once every twodays, every three days, every five days, once a week, once or twice amonth, and the like. In some embodiments, the amount, forms, and/oramounts of the different forms may be varied at different times ofadministration based on the neural state and/or prediction of theseizure.

The following description provides one example of a predictive algorithmthat may be used to monitor the patient's neural state to monitor theeffect of acute dosages of AEDs. As can be appreciated any of theaforementioned predictive algorithms may be used by the presentinvention to predict the onset of a seizure, and the present inventionis not limited to the following example.

Chronic dosages of anti-epileptic drugs (AEDs) have been shown toimprove seizure control in patients with partial epilepsy. Previousstudies have indicated that the development and resolution of seizuresare associated with measurable changes in the spatiotemporal dynamics ofEEG signals. The present pilot study is designed to show the effect ofan acutely administered dosage of an AED on the patient's propensity fora future seizure, as characterized by a patient's neural state. In oneembodiment, the patient's neural state is characterized by classifyingthe patient's dynamical characteristics of the EEG signals.Specifically, an acute dosage (the FDA approved dosage or some reductionof the FDA approved dosage) of select AEDs or other suitablepharmacological agents (referred to in this example as “AED”), underspecific dynamical conditions, will modulate the neural state or EEGdynamics, maintain the neural state in a desired range, keep the neuralstate from progressing outside a desired range, preventing the neuralstate from entering a critical range, or if outside the desired range toreturn to the desired range, which comprise states in which seizures areless likely to occur. In one embodiment, this neural state may becharacterized by higher values of the T-index, a measure that indicateslower dynamical similarity in the EEG signal derived from electrodeslocated over widespread areas of the cerebral cortex. However, in otherembodiments, the patient's propensity for a future seizure may becharacterized by some other features, including any of the other neuralstate features described above.

The exact EEG profile, optimum feature(s) measured to characterize theneural state, and the particular AED for treatment vary from patient topatient or between patient groups. It is thus possible to analyze thespecifics of the EEG signal measured, the optimum drug dosage, correlatedosages to the prediction horizon and optimize the therapy utilized,whether a drug or other therapy, for an individual patient orsub-populations of patients. The effect of AEDs on dynamicalcharacteristics of EEG signals are analyzed to determine if an acutedosage of a particular AED during the interictal state results in aperturbation of the neural state (e.g., an increase of the T-index),which may reduce the patient's propensity for a seizure and provide aprotective effect against the occurrence of seizures. It can also helpidentify for which patients this drug and prediction algorithm are mosteffective.

Specific Aim 1:

Determine the EEG electrode groups that show the most convergence ofSTLmax values prior to the first recorded seizure and also demonstratethe resetting after the seizure. These electrode groups are then usedfor detecting the fluctuations in T-index.

Specific Aim 2:

Determine the optimal parameter settings for an automated seizureprediction system. The determination is based on the evaluation of thesensitivity and specificity of the prediction algorithm.

Specific Aim 3:

Identify patients who exhibit consistent identifiable correlationsbetween T-index fluctuations and seizure propensity.

Specific Aim 4:

In patients that show meaningful T-index fluctuations, determine whetheracute dosages of AEDs influence the T-index.

Epileptic seizures are typically preceded and accompanied bycharacteristic dynamical changes detectable in the spatiotemporalpatterns of the EEG. Specifically, seizures are preceded by convergencein the value of STLmax among specific EEG electrode sites, beyond thatseen normally in the interictal phase. This can be observed bymonitoring STLmax values over time in EEG recordings obtained usingintracranial or scalp electrodes. See U.S. Pat. No. 6,304,775.

The convergence of STLmax among the critical electrodes can be measuredby calculating a T-index, a normalized mean difference of the STLmaxbetween selected electrodes. Thus, prior to a seizure, there is adecrease in the T-index, more than its normal fluctuation, as the valuesof STLmax converge.

During a complex partial or secondarily generalized seizure recordedfrom intracranial EEG electrodes, STLmax values calculated from allelectrode sites converge to a common value and fall abruptly in value.The postictal state is characterized by a gradual increase in the valuesof STLmax to the values characteristic of the interictal state and adivergence in values among electrode sites. This divergence is reflectedby a rise in the value of the T-index.

Not intending to be limited to one mechanism of measuring neural state,it is believed that the convergence of STLmax values represents adynamical entrainment among large areas of the epileptic brain. Further,it is believed that it is this entrainment that increases the likelihoodof a seizure developing. This suggests that an intervention aimed atreducing the convergence, causing the T-index to increase, offers aprotective effect and decreases the propensity of a seizure occurring.Further, as described herein, acute dosages of AEDs exert ananticonvulsant effect by altering brain dynamics and increasingdisentrainment of regions in the brain.

The spatiotemporal dynamic effects of an acute dosage of an AED thatinterface with automated seizure prediction algorithms are investigated.The prediction algorithm may be based on dynamical analysis of EEGsignals, optimization algorithms for selection of critical electrodegroups, and statistical pattern recognition methods, as described above.

One embodiment of the seizure prediction algorithm is based on the ideathat seizures occur in a dynamical state characterized by comparativespatiotemporal order, which can be measured by the T-index, a value thatindicates standard mean difference in the value of STLmax (an indicatorof how ordered the signal from an individual channel is during a giventime window), among multiple EEG electrode sites. A low T-index reflectsconvergence of STLmax values among electrode sites, indicating spatialorder.

In assessing the usefulness of the T-Index as a viable feature forcharacterizing the neural state, investigations in the rodent chroniclimbic epilepsy model indicate that direct electrical stimulation to thehippocampus when the T-index is low can cause the T-index to rise backto higher values and delay seizure onset. In FIG. 18, the upper tracingslabeled “voltage” depict 30 seconds of EEG (recorded from the leftfrontal cortex LF, right frontal cortex RF, left hippocampus LH andright hippocampus RH) before stimulation (left) and 30 seconds afterstimulation (right) of the left hippocampus. Note the change in EEG to aless ordered (more chaotic) appearing pattern. The middle plot showsSTLmax profiles of EEG signals derived from the same electrodes, over a35 minute period. Note that the hippocampal stimulus was givenapproximately 25 minutes into the tracing. The lower plot is a T-index,indicating the standard mean difference of STLmax values between the LHelectrode and each of the other electrodes. The T-index for LF and RFconverge approximately 15 minutes into the trace (fall below the lowerthreshold LT). After the stimulus, the T-index for LF and RF are backabove the upper threshold UT. Acute dosages of selected AEDs can beanalyzed for similar effects on the T-Index in patient sub-populations.

FIG. 19 shows a seizure pattern observed in a rodent with chronic limbicepilepsy undergoing continuous EEG monitoring with automated seizurewarning in place. During the Pre-Stimulus Block of time, the meanseizure interval was 2.7 hours (1.0 sd). During the stimulus block, theleft hippocampus was stimulated for 10 seconds at 125 Hz each time theT-index fell below the lower threshold. During the Stimulus Block oftime, the mean seizure interval increased to 7.2 hours (1.3 sd). Upondiscontinuation of stimulation, the mean seizure interval dropped backto 2.4 hours ((0.7 sd). This suggests that electrical stimulation notonly reset the T-index to higher values, but also served to reduceseizure frequency. Acute dosages of AEDs can be analyzed for similareffects on T-Index in various patient sub-populations.

The protocol may be conducted in 2 phases. The purpose of Phase 1 is toidentify patients who consistently show a significant change in theT-index, derived from EEG recordings derived from scalp electrodes,prior to their complex partial or generalized seizures. The subset ofEEG electrode sites that provide the most meaningful data by training anautomated computer-based seizure prediction algorithm may be identified.In Phase 2, an acute dosage of an AED is taken during the interictalphase to increase the T-index and reduce the risk of a seizure.

Phase 1:

The goal of phase 1 is to train the automated seizure predictionalgorithm, that is, to determine the critical electrode groups formonitoring and the optimal parameter setting of the algorithm. See U.S.Patent Application Publication Nos. US2004/0127810 A1 andUS2004/0122335. At the time of admission, the patient's interval,medical and neurological history, is obtained and physical andneurological examinations are performed. Each patient may be accompaniedby a family member or close friend who is familiar with their seizuredisorder. This person assists by alerting the staff in the event thatthe patient has a seizure and also assists the patient, as needed.

Training of the ASPA includes determining (1) the critical electrodegroups that show the greatest change between interictal levels and thosefound during a seizure, and (2) the proper parameters of the algorithmthat achieve an acceptable performance for recognizing uniquespatiotemporal dynamical pattern for the specific patient. At least 3seizures should be recorded during this phase to train the ASPA.

Patients that had at least 3 seizures and for whom seizures wereconsistently preceded by a definite drop in the T-index stay in thestudy to complete phase 2, another 7 day long hospital stay. If notpossible, patients are discharged and re-admitted within one month forphase 2. Eighty percent of patients completing phase 1 will likely beeligible for phase 2.

Phase 2:

The purpose of this phase of the study is to determine whether taking anacute dosage of a particular AED, during the preictal phase elevates theT-index, which may provide a protective effect against the occurrence ofseizures. Phase 2 occurs immediately following, or within one monthafter, completion of phase 1.

The ASPA system may monitor patient's EEG recordings continuously for 7days. When the ASPA detects a drop in the T-index below the lowerthreshold value, it activates a warning device (such as a patientcommunication assembly 18—FIG. 2) which will alert, instruct and/orprovide a recommendation to the patient and anyone else in the room withan audio and visual alert from a personal computer in the patient's roomdesignated for this study. The patient, patient's companion, or theproper attending medical staff then administers a prescribed AED, assuggested by the ASPA or the patient's caregiver.

For a randomly assigned half of the patients, the first 3.5 days are“No-AED” trial and the last 3.5 days “AED” trial, and vice versa for theother half of the patients. When a patient is under “AED” trial, thepatient, guardian or kin, or appropriate tending medical staff memberrespond to the algorithm's seizure prediction alert and provide an acutedosage of the AED to the patient. When a patient is under “No-AED”trial, no AED is given to the patient.

This phase investigates how dynamical properties of EEG are changed byan acute dosage of an AED. To accomplish this, one or more onlinereal-time ASPA software is interfaced with the EEG acquisition system.While the acquisition system is recording EEG from the patient, theseizure prediction algorithm simultaneously analyze the dynamicalproperties of the EEG and the dynamical measures are displayed on aninterfaced computer. During the “AED” trial, when the neural state(e.g., dynamical measures T-index of STLmax) indicate that the patienthas an elevated propensity for a seizure, a “Warning” sign or“Instruction/recommendation” is displayed on the analysis computer andan AED may be administered by the patient, patient's guardian or kin, orthe proper attending medical staff. During the “No-AED” trial, an AED isnot administered. Since the T-index values are low at the time when a“Warning” or “Instruction/recommendation” is given, the T-index valuesshould be increased to a higher level (as observed during normalinterictal state) by AED intervention.

The EEG signals are acquired using a standard clinical data acquisitionmachine at a sampling rate of 400-500 Hz and are transferred offlineinto one of the research servers for post-hoc analysis. Medicationstaken, seizures reported or observed and level of awareness aredocumented during each phase of the study.

Statistical Analysis:

To test the hypothesis, for each patient, the proportion of AEDinterventions that significantly elevate the T-index values areestimated, as well as the proportion of interventions that significantlyelevate the T-index for a time period equal to or greater than theestimated duration for which the patient is at an elevated propensityfor a seizure, as derived from previous studies. Same proportions under“No-AED” trial are also estimated and are used as controlled outcomes ofthe study. Interventions (AED or No-AED) are repeated at least 10 timesin each trial for the estimation of the proportions.

Without the assumption of underlying distribution, a two-sided Wilcoxonsigned-rank test (a nonparametric analogue to the paired-T test) isapplied to test the mean proportion difference between “No-AED” trialsand “AED” trials. Each outcome proportion is estimated from at least 10trials in each patient. Therefore, we will have a response table similarto that shown in FIG. 20.

Randomization: Each patient is randomly assigned to one of the twogroups of treatment order: “No-AED” to “AED” and “AED” to “No-AED”.

Sample Size: (N=16, 8 of which receive “No-AED” treatment first, and theremaining 8 receive “AED” treatment first). For an overall two-samplepair-T test, a study of 16 subjects under a normal distributionalset-up, with significance level of 0.05, has 96% power to detect adifference (effect size) of 1.0 standard deviation in the dependentvariable from the null hypothesized value of 0.0. Given a sample size of16, the power of the exact signed-rank test to detect a mean of 1.0standard deviations from the null hypothesized value of zero, P<0.05two-sided is about 95%. (Based on 100,000 simulations, the empiricalpower was 94.8%). A t-test would have 96% power, but is not robust todepartures from normality, whereas the sign-ranked test yields a validp-value under any symmetric null distribution about zero for the paireddifference.

CONCLUSION

While all the above is a complete description of the preferredembodiments of the inventions, various alternatives, modifications, andequivalents may be used. The system of the present invention may be usedas an add-on to existing neural stimulation devices. For example, theCyberonics VNS Therapy system or the Medtronic Intercept DBS Therapy maybe improved by using the systems and methods of the present invention.The systems of the present invention may be used to monitor thepatient's neural state and once the system determines a heightened riskof a seizure, the patient may be instructed to activate the VNS therapy.

What is claimed is:
 1. A method of preventing an epileptic seizurecomprising: a first characterizing step, comprising characterizing apatient's propensity for an onset of a future epileptic seizure;communicating to the patient and/or a health care provider a firsttherapy recommendation, wherein the first therapy recommendation isselected from a plurality of therapy recommendations based on thepatient's propensity for the onset of the epileptic seizurecharacterized in the first characterizing step; a second characterizingstep after said first characterizing step, comprising characterizing thepatient's propensity for an onset of a future epileptic seizure; andcommunicating to the patient and/or a health care provider a secondtherapy recommendation, wherein the second therapy recommendation isdifferent than the first therapy recommendation and is selected from theplurality of therapy recommendations based on the patient's propensityfor the onset of the epileptic seizure characterized in the secondcharacterizing step.
 2. The method of claim 1 wherein the first andsecond characterizing steps each comprise characterizing a neural stateof a patient.
 3. The method of claim 2 wherein first and secondcharacterizing steps each comprise measuring one or more patientdependent parameters.
 4. The method of claim 3 wherein the patientdependent parameters comprise EEG signals.
 5. The method of claim 4wherein the measured EEG signals are measured using an intracranialelectrode array.
 6. The method of claim 1 wherein the first and secondtherapy recommendations each comprise an instruction to administer anacute dosage of an anti-epileptic agent.
 7. The method of claim 6wherein the first and second therapy recommendations each comprisedosage information for the anti-epileptic agent, wherein the dosage isselected based on the patient's characterized propensity for the onsetof the future epileptic seizure.
 8. The method of claim 7 wherein thepatient's characterized propensity for the onset of the future epilepticseizure is indicative of a seizure onset time parameter, the dosageinformation comprising a dose inversely related to the time parameter.9. The method of claim 7 wherein the patient's characterized propensityfor the onset of the future epileptic seizure is indicative of aprobability parameter, the dosage information comprising a dose directlyrelated to the probability parameter.
 10. The method of claim 7 whereinthe dosage information corresponding to at least one of the first andsecond therapy recommendations is a dose selected to be lower than anFDA-approved dose for the anti-epileptic agent.
 11. The method of claim7 wherein the dosage information corresponding to at least one of thefirst and second therapy recommendations is a dose selected to be higherthan an FDA-approved dose for the anti-epileptic agent.
 12. The methodof claim 7 wherein the dosage information corresponding to at least oneof the first and second therapy recommendations is a dose selected to beequivalent to an FDA-approved dose for the anti-epileptic agent.
 13. Themethod of claim 6 wherein the first and second therapy recommendationseach specifies a form of the anti-epileptic agent, a formulation of theanti-epileptic agent, and/or a route of administration of theanti-epileptic agent.
 14. The method of claim 1 wherein the first andsecond therapy recommendations each comprises electrical stimulation ofa vagus nerve.
 15. The method of claim 1 wherein: the first therapyrecommendation comprises an instruction to administer a first dosage ofan anti-epileptic agent; and the second therapy recommendation comprisesan instruction to administer a second dosage of the anti-epilepticagent, said second dosage being different than the first dosage.
 16. Themethod of claim 1 wherein: the first therapy recommendation comprises aninstruction to administer a first dosage of an anti-epileptic agent; andthe second therapy recommendation comprises an instruction to administera second dosage of the anti-epileptic agent greater than the firstdosage, wherein the patient's propensity for the onset of the epilepticseizure characterized in the second characterizing step is greater thanthe patient's propensity for the onset of the epileptic seizurecharacterized in the first characterizing step.
 17. The method of claim1 wherein: the first therapy recommendation comprises an instruction toadminister a dosage of a first pharmacological agent; and the secondtherapy recommendation comprises an instruction to administer a dosageof a second pharmacological agent different than the firstpharmacological agent.